R E V I EW

TRAPPopathies: An emerging set of disorders linked tovariations in the genes encoding transport protein particle(TRAPP)-associated proteins

Michael Sacher1,2 | Nassim Shahrzad3 | Hiba Kamel1 | Miroslav P. Milev1

1Department of Biology, Concordia University,

Montreal, Quebec, Canada

2Department of Anatomy and Cell Biology,

McGill University, Montreal, Quebec, Canada

3Department of Medicine, University of

California, San Francisco, California

Correspondence

Michael Sacher, Department of Biology,

Concordia University, Montreal, QC, 7141

Sherbrooke Street West Room SP-457.01

Montreal, Quebec Canada H4B1R6 Canada.

Email: michael.sacher@concordia.ca

Funding information

Concordia University; Natural Sciences and

Engineering Research Council of Canada;

Canadian Institutes of Health Research

The movement of proteins between cellular compartments requires the orchestrated actions of

many factors including Rab family GTPases, Soluble NSF Attachment protein REceptors

(SNAREs) and so-called tethering factors. One such tethering factor is called TRAnsport Protein

Particle (TRAPP), and in humans, TRAPP proteins are distributed into two related complexes

called TRAPP II and III. Although thought to act as a single unit within the complex, in the past

few years it has become evident that some TRAPP proteins function independently of the com-

plex. Consistent with this, variations in the genes encoding these proteins result in a spectrum

of human diseases with diverse, but partially overlapping, phenotypes. This contrasts with other

tethering factors such as COG, where variations in the genes that encode its subunits all result

in an identical phenotype. In this review, we present an up-to-date summary of all the known

disease-related variations of genes encoding TRAPP-associated proteins and the disorders

linked to these variations which we now call TRAPPopathies.

KEYWORDS

Golgi, guanine nucleotide exchange factor, intellectual deficit, membrane traffic, muscular

dystrophy, neurodevelopmental disorders, Rab, secretory pathway, TRAPP, variants

1 | MEMBRANE TRAFFICKING FACTORS

Correct protein localization to the various intracellular compartments

is of critical importance to the proper functioning of a cell. This pro-

cess, referred to as membrane traffic, requires numerous proteins and

complexes to ensure that the organellar proteins are sorted in an

appropriate spatiotemporal manner. Defects in this process can result

in a variety of human disorders.1,2

The process starts with the collection of cargo at regions of the

donor compartment that deform to generate a transport carrier. Mem-

brane deformation is achieved by the actions of a complex of proteins

referred to as coat proteins. In the early biosynthetic pathway, the

coat protein complex called COP II participates in the formation of

vesicles from the endoplasmic reticulum (ER),3 while the coat protein

complex coatomer/COP I functions at the level of the Golgi.4 Recruit-

ment of these complexes to their respective membranes is mediated

by the activation of small GTP-binding proteins of the Rab family

called Sar1 (which recruits COP II) and Arf1 (which recruits COP I).5

The carriers also contain membrane proteins of the Soluble NSF

Attachment protein REceptor (SNARE) family that are intimately

involved in the fusion of the carrier with the target membrane. Once

uncoated, the SNARE proteins on the carrier and target membrane

interact such that a trans-SNARE complex is formed, consisting of

three Q-SNAREs and one R-SNARE.6 Zippering of the so-called

SNARE-domain proximal to the membrane-spanning domain provides

the energy to drive membrane fusion.7,8 Although originally proposed

to provide specificity in carrier-target membrane recognition,9 it is

unlikely that SNAREs alone impart this specificity, and other proteins

such as Rabs and tethers/tethering factors have been implicated.

Tethering factors are proteins that are thought to participate in

the initial contact between the carrier and the target membrane.

These factors have been divided into two classes: coiled-coil tethering

factors and multisubunit tethering factors.10,11 The coiled-coil pro-

teins contain heptad repeats allowing for the formation of amphi-

pathic helices that interact with other such proteins to form a

relatively strong tether that can bridge two membranes. The multisu-

bunit tethering factors are heteromeric protein complexes that partici-

pate in some aspect of tethering the apposed membranes prior to

fusion. These complexes function at virtually all organelles of the bio-

synthetic pathway11 (Table 1).

Received: 1 February 2018 Revised: 23 August 2018 Accepted: 26 August 2018 Uncorrected manuscript published: 27 August 2018

DOI: 10.1111/tra.12615

Traffic. 2018;1–22. wileyonlinelibrary.com/journal/tra © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1

2 | THE TRAPP FAMILY OF MULTISUBUNITTETHERING FACTORS

The aforementioned complexes were originally believed to physically

tether apposing membranes. However, this has in fact only been

shown to be the case for the HOPS complex.12 While these com-

plexes may yet be shown to act as tethers, it remains possible that

their role in the tethering process is indirect. Thus, understanding the

precise function(s) of these complexes is a crucial area for future

research.

One well-studied multisubunit tethering factor is the TRAnsport

Protein Particle (TRAPP) family of complexes, first identified in yeast.

While initially thought to be a single complex composed of

10 subunits,13 it became apparent that there were in fact three related

complexes, each containing a common core of proteins14,15

(Figure 1A). The yeast TRAPP I complex is composed of the subunits

Trs20, Bet5, two copies of Bet3, Trs23, Trs31 and Trs33. These sub-

units represent the core of all three TRAPP complexes and are the

only proteins in TRAPP I. The TRAPP II and III complexes contain the

core with four additional subunits (Tca17, Trs65, Trs120 and Trs130)

TABLE 1 Localization and functions of the mammalian multisubunit tethering factor complexes

Multisubunittetheringfactor Localization Function(s) References Notes

Dsl1 Endoplasmic reticulum (ER) Golgi-to-ER traffic,maintenance of Golgimorphology

Aoki et al130; Sun et al131;Arasaki et al132

May have a role in ER-to-Golgitraffic132,133; functions ofindividual proteins of thecomplex are varied134

COG Cis and medial Golgi, tips andrims of Golgi cisternae, cisand trans Golgi networks,COPI vesicles

Maintenance of Golgimorphology, Golgiretrograde trafficking,tethering of COP I vesiclesto the Golgi, effector ofRab1A and Rab30

Suvorova et al135; Ungaret al127; Oka et al136; Zolovand Lupashin137; Vasileet al138; Miller et al139

Function in retrogradetransport is inferred throughthe subunit-mutantphenotypes (eg,glycosylation failures,vesicle accumulation) andinteraction with proteins(eg, COPI)

TRAPP II Early Golgi, COP I-coatedvesicles, lipid droplets,centrosomal vesicles

COPI vesicle tethering to theearly Golgi; Rab1 and Rab18GEF, intra-Golgi traffic, lipiddroplet homeostasis,ciliogenesis

Yamasaki et al27; Westlakeet al69; Li et al28

Yu et al140 demonstrate a rolefor TRAPPC3 in homotypicCOP II vesicle fusion but itis unclear if the protein isfunctioning outside ofTRAPP nor which TRAPPcomplex is implicated;centrosome localization isdependent upon serumstarvation

TRAPP III Early Golgi, ER exit sites,tubulated recyclingendosomes

ER-to-Golgi traffic, COP IIrecruitment to ER,autophagy

Scrivens et al17; Lamb et al122;Zhao et al19

Tubulated recyclingendosomes were producedby TBC1D14overexpression

CORVET Rab5-positive earlyendosomes

Early endosome tethering andfusion

Perini et al141; van der Kantet al142

HOPS Late endosomes/lysosomes,autophagosomes

Late endosome-lysosomefusion, Rab5-to-Rab7conversion on endosomes,autophagosome-lysosomefusion

Kim et al143; Rink et al144;Jiang et al145; van der Kantet al142

Mammalian HOPS is recruitedto Rab7 positivemembranes by RILP

CHEVI Recycling endosomes, lateendosomes

Endosome recycling to apicalmembranes, lateendosome-lysosome fusion

Smith et al146; van der Kantet al142; Galmes et al147

Localization to late endosomesis seen when co-expressedwith RILP

Exocyst Plasma membrane, trans-Golginetwork (TGN), recyclingendosomes, primary cilium

Traffic to the plasmamembrane, basolateral andapical transport in polarizedcells, ciliogenesis, GLUT4trafficking to cell surface

Yeaman et al148; Inoueet al149; Rogers et al150; Anget al151; Oztan et al152; Liuet al153; Grindstaff et al154;Zuo et al155

GARP TGN, endosomes or smallvesicles en route to theTGN

Recycling to the TGN, mightalso participate inendosome recycling to theplasma membrane

Liewen et al156; Perez-Victoriaet al157,158; Schindleret al159

EARP Recycling endosomes Fast endosome recycling tothe plasma membrane oftransferrin receptor

Schindler et al159 Predominant localization wasto Rab4A-positiveendosomes; also shown tofunction in sorting todense-core vesicles inCaenorhabditis elegans160

Due to space limitations, this table is not to be considered an exhaustive list, but rather a general summary. Comprehensive reviews are available for mostof these complexes.

2 SACHER ET AL.

in TRAPP II, and one additional subunit (Trs85) in TRAPP III.16 All of

the yeast subunits are conserved in higher eukaryotes including

humans (Table 2), while humans and other metazoa contain additional

associated proteins for which no Saccharomyces cerevisiae homologue

has been identified.17 Curiously, a TRAPP I-equivalent complex is yet

to be reported in humans, although human TRAPP II and III complexes

have been described.18,19 The human complexes contain a similar core

of proteins (TRAPPC1, TRAPPC2, two copies of TRAPPC3, TRAPPC4,

TRAPPC5 and TRAPPC6). In addition to this core, TRAPP II also con-

tains TRAPPC9 and TRAPPC10, while TRAPP III contains the core

with TRAPPC8, TRAPPC11, TRAPPC12 and TRAPPC13 (Figure 1B).

Several studies have implicated the TRAPP complexes in the teth-

ering process.15,20,21 It is noteworthy that their role as bona fide

tethers has yet to be definitively demonstrated because these studies

relied largely on crude biochemical fractions, genetics and microcopy

phenotypes. Indeed, their contribution to this process awaits studies

with purified proteins and membranes, and TRAPP complexes may

yet be revealed to function indirectly in this process. As yeast TRAPP

complexes were shown to bind to the small GTPase Ypt1p in its

nucleotide-free state,22 it was speculated that TRAPP could act as a

guanine nucleotide exchange factor (GEF) for this GTPase, converting

it to its active form. Indeed, all three TRAPP complexes have been

reported to have GEF activity toward Ypt1p,14,22,23 and more recently

the TRAPP II complex was shown to have robust GEF activity toward

Ypt31 and the related GTPase Ypt32.24 The GEF activity of recombi-

nant TRAPP I was shown to be dependent upon all of the core pro-

teins except for Trs33 and Trs20.25 A subsequent study revealed the

mechanism for this activity and the key role that the carboxy-terminus

of Bet3 plays in destabilizing the GDP nucleotide bound to the

GTPase.26 Consistent with one study in yeast that demonstrated Ypt1

GEF activity for TRAPP II,26 Yamasaki et al27 demonstrated that the

human TRAPP II complex had GEF activity toward the human Ypt1

homologue called Rab1 but did not report any TRAPP-dependent GEF

activity toward the human homologue of Ypt31 or Ypt32 called

Rab11. In addition, GEF activity of human TRAPP II toward Rab18 has

also been reported.28 It remains unclear as to what, if any, GEF activ-

ity the human TRAPP III complex displays. A recent study focused on

the Drosophila TRAPP complexes demonstrated GEF activity toward

Rab1 and Rab11 but not for Rab18.29

Work predominantly using the yeast model system has suggested

that TRAPP I binds to partially uncoated, ER-derived transport vesi-

cles, and this interaction is mediated by the COP II protein Sec23.20

Subsequent phosphorylation of Sec23 by the Golgi-localized kinase

Hrr25 (casein kinase 1δ in humans) releases TRAPP I from the vesicle

allowing fusion to proceed, a process that is conserved in humans.30

In spite of the elegant work performed on yeast TRAPP I, biochemical

studies on the yeast Trs23 protein raised the possibility that TRAPP I

is an in vitro artifact and may not exist in living cells,31 a notion that

was recently supported by cell biological studies.32 This is consistent

with the lack of identification of a mammalian TRAPP I equivalent and

the inability to express recombinant human TRAPP I, while expression

of recombinant yeast TRAPP I has been accomplished.25 Recent evi-

dence suggests that yeast TRAPP III can fulfill the functions of

TRAPP I.32

FIGURE 1 The yeast and human TRAPP complexes. Cartoons of the

three yeast complexes (A) and the two known mammalian complexes(B) are shown. The core of proteins found in all complexes is coloredin cyan. The arrangement of the subunits within this core is based onits known organization.25,26 The placement of Trs85 in yeast TRAPPIII is based on biochemical and single-particle electron microscopicdata.14,41 The placement of Trs130 and Trs120 is based on genetic,mutational and yeast two-hybrid data.34,36,57,236 It should be notedthat the single-particle electron microscopic data suggests theopposite arrangement,37 a discrepancy that still needs to be resolved.

In the mammalian cartoons, the placement of TRAPPC8 is based onthe homology to the yeast protein as well as one study indicating thatit interacts with TRAPPC2.43 The placement of TRAPPC10 is basedon a study65 that suggests it interacts with TRAPPC2L, and theplacement of TRAPPC9 is based on a biochemical study43

TABLE 2 Conservation of yeast and human TRAPP proteins

Yeast protein Human protein Percent identity/similarity

Bet5 TRAPPC1 33/54

Trs20 TRAPPC2 34/52

Tca17 TRAPPC2L 24/43

Bet3 TRAPPC3, C3L 56/76, 51/73

Trs23 TRAPPC4 29/44

Trs31 TRAPPC5 31/52

Trs33 TRAPPC6A,B 35/51, 33/47

Trs65a

Trs85 TRAPPC8 28/49

Trs120 TRAPPC9 25/44

Trs130 TRAPPC10 24/45

TRAPPC11 —

TRAPPC12 —

TRAPPC13

a Kluyveromyces lactis and Candida glabrata homologues share homology(31% identity/45% similarity) over a relatively small region withTRAPPC13 as revealed by PSI-BLAST.34

SACHER ET AL. 3

In yeast TRAPP II, variants in trs130 were implicated in antero-

grade traffic through or from the Golgi while variants in trs120 only

affected traffic between endosomes and the Golgi,15,33 suggesting dif-

ferent functions for the encoded proteins within the same complex. A

physical interaction was also reported between TRAPP II and COP I in

both yeast and higher eukaryotes.27,28,33 Although non-essential in

yeast, Trs65 was reported to be required for optimal TRAPP II activity,

organization and assembly.34–37 Curiously, although human TRAPP II

was shown to activate Rab1 that is required for ER-to-Golgi traffic,

depletion of the TRAPP II subunit TRAPPC10 (the human homologue

of Trs130) did not affect this step of the biosynthetic pathway.27

The yeast TRAPP III complex contains a single additional subunit,

Trs85, that associates with the core. While originally thought to form

a complex functionally distinct from that of TRAPP I and localized as a

single punctum on the preautophagosomal structure,14,38,39 several

studies implicated Trs85 in ER-to-Golgi traffic15,40 and, using a

brighter fluorescent tag, the TRAPP III complex was shown to also

localize to the Golgi.32 Thus, yeast TRAPP III likely functions in both

ER-to-Golgi traffic and autophagy. Biochemical and structural studies

have shown that the Trs20 protein and its mammalian homologue

TRAPPC2 are required for the attachment of Trs85 (and its mamma-

lian homologue TRAPPC8) to the complex.41–43 In addition to

TRAPPC8, the human TRAPP III complex also contains proteins called

TRAPPC11 (also called c4orf41) and TRAPPC12 (also called TTC15)

that have no readily identifiable yeast homologues.17 This complex

was shown to function in an early stage of the secretory pathway17

and to recruit part of the COP II vesicle coat that functions in this

pathway.19 Like the yeast TRAPP III complex, the human complex was

also implicated in autophagy44,45 (D. Stanga, Q. Zhao, M. Milev,

D. Saint-Dic, C. Mallebrera and M. Sacher, manuscript in preparation).

3 | TRAPPOPATHIES: DISEASESASSOCIATED WITH VARIANTS IN TRAPPPROTEINS

Although assumed to act as a single unit, variations in proteins of the

TRAPP complexes result in distinct disorders with overlapping pheno-

types, suggesting that either portions of the complexes have separate

functions or TRAPP proteins have functions outside of the complex

that are specific to each protein. Indeed, for a number of the TRAPP

proteins linked to human health, the latter appears to be the case. The

following sections will detail disorders linked to known variants in

TRAPP-associated proteins that we now refer to collectively as

TRAPPopathies, and how these variants may result in the distinct phe-

notypes reported. We briefly discuss what is known about each pro-

tein and its structure, and then discuss clinical phenotypes, attempting

to relate them to either a TRAPP or a non-TRAPP function. A sum-

mary of all known TRAPP gene variants to date, the resulting protein

variants and their associated phenotypes is presented in Table 3, eas-

ily allowing the readers to map the variant to the protein or a domain

within the affected protein. Readers are directed to several earlier

reviews touching upon some aspects of TRAPP proteins in disease in

a more concise manner.16,46

3.1 | TRAPPC2 (MIM 300202)

The yeast Trs20 protein was identified as a component of TRAPP in

the initial report of the yeast TRAPP complex.13 This protein, display-

ing 34% identity and 54% similarity with human TRAPPC2 (Table 2),

was found in substoichiometric amounts in the yeast TRAPP I com-

plex, and was subsequently shown to be required for the stable

attachment of the yeast protein Trs85 to the TRAPP III complex.41,42

The human protein, going by the names sedlin, SEDL, TRAPPC2 and

hTrs20, can functionally replace its yeast homologue,47 suggesting an

evolutionarily conserved function for the protein. Consistent with its

conserved function, TRAPPC2 was shown to be required for the asso-

ciation of both TRAPPC8 and TRAPPC9 with the human TRAPP

complex.43

The crystal structure of TRAPPC2 was solved and shown to

resemble that of the amino-terminal regulatory domain of the SNARE

proteins Sec22 and Ykt6.48 This similarity led to the suggestion that

TRAPPC2 either regulated the function of SNARE proteins and/or

acted as a protein adaptor, both of which have been supported by

subsequent studies in yeast and higher eukaryotes.41–43 The overall

fold of TRAPPC2 and the regulatory domain of these SNARE proteins

have been referred to as longin-domain folds which are found in many

trafficking proteins.49 Interestingly, several other TRAPP core proteins

also adopt a three-dimensional structure similar to that of

TRAPPC2.25 A study that elucidated the architecture of the core pro-

teins of TRAPP (TRAPPC1, TRAPPC2, TRAPPC3, TRAPPC4, TRAPPC5

and TRAPPC6) suggested that one surface of TRAPPC2 was involved

in interactions with TRAPPC5, but the remainder of the protein was

well-suited to mediate other interactions,25 consistent with its pro-

posed role as a TRAPP protein adaptor.

In addition to its function in membrane trafficking by association

with the TRAPP complex, TRAPPC2 was identified as a protein called

MIP-2a that regulates the activity of the transcriptional repressor pro-

tein MBP-1.50 MIP-2a appears to arise from transcription of what was

thought to be a TRAPPC2 pseudogene on chromosome 19.51 The

expression of MIP-2a differs from that of TRAPPC252 although the

functional significance of this is unclear as the two proteins are identi-

cal. A more recent study found that MIP-2a was a target of the anili-

noquinazoline Q15, a compound that induces apoptosis.53 Q15

disrupted the interaction between MIP-2a and MBP-1 leading to an

accumulation of the latter in the nucleus that resulted in an inhibition

of c-myc transcription and, ultimately, cell death.

In 2012, Venditti et al presented an elegant model for the role of

TRAPPC2 in the regulation of the export of collagen from the ER.54

Emergence of a vesicle at the ER is dependent upon the activity of

the GTPase Sar1.55 TRAPPC2 enhances the inactivation of Sar1 at ER

exit sites,54 thereby preventing membrane constriction and allowing

nascent vesicles to grow to a size sufficient to accommodate the large

procollagen fibrils. Interestingly, TRAPPC2 is recruited specifically to

the sites of procollagen export via an interaction with the procollagen

receptor TANGO1.

Although its inclusion as a TRAPP component was originally

inferred by analogy to its yeast homologue Trs20, TRAPPC2 was

shown to be present in a high-molecular-weight fraction of a size

exclusion column.56 Subsequent studies showed that the protein

4 SACHER ET AL.

TABLE

3Variantsin

TRAPPge

nes

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

TRAPPC2

MIM

:300202

c.139G>T

p.Asp47Tyr

SEDT

313400

Ged

eonet

al59

c.218C>T

p.Se

r73Le

uSE

DT

313400

Shaw

etal61;G

edeo

net

al59;

Zho

uet

al62

Oneindividualalso

has

Leber

hered

itaryopticneu

ropathydue

toamtD

NAmutation

c.239A>G

p.His80Arg

SEDT

313400

Linet

al161

c.248T>C

p.Phe

83Se

rSE

DT

313400

Grune

baum

etal60

c.389T>A

p.Val130Asp

SEDT

313400

Ged

eonet

al59

c.53-54de

lTT

p.Phe

18*

SEDT

313400

Ged

eonet

al58,59

c.61G>T

p.Glu21*

SEDT

313400

Xiaet

al162

c.167C>A

p.Se

r56*

SEDT

313400

Fiedler

etal163

c.182T>A

p.Le

u61*

SEDT

313400

Ged

eonet

al59

c.210G>A

p.Trp70*

SEDT

313400

Christieet

al164

c.210G>Aan

dc.325de

lTp.Trp70*an

dp.

Ser110Glnfs*2

SEDT

313400

Fiedler

etal165

Oneoftw

oindividualswithtw

oseparatevarian

tsin

thege

ne

c.209G>A

p.Trp70*

SEDT

313400

Zhu

etal166;C

aoet

al167

c.271C>T

p.Gln91*

SEDT

313400

Ged

eonet

al59

c.329C>A

p.Se

r110*

SEDT

313400

Shie

tal168

c.345_3

46de

lTG

p.Tyr115*

SEDT

313400

Fiedler

etal165

c.364C>T

p.Arg122*

SEDT

313400

Christieet

al164

c.391C>T

p.Gln131*

SEDT

313400

Takah

ashi

etal169

c.6de

lp.Se

r4Alafs*5

SEDT

313400

Gomes

etal170

Individualisdouble

heterozygo

us

forTR

APPC2an

dFG

FR3

c.1138G>Awithaco

mpound

phen

otypeofachondrodysplasia

andSE

DT

c.94-2A>G

p.Asp32Ile

fs*2

SEDT

313400

Fuk

umaet

al171

Predictedsplicevarian

tin

the

intronupstream

ofex

on4;

predictedto

resultin

skippingof

exon4

c.99de

lCan

dc.236-5_8

delATTA

p.His34Ile

fs*4

SEDT

313400

Fiedler

etal165

Oneoftw

oindividualswithtw

oseparatevarian

tsin

thege

ne;

the

intronicdeletionispredictedto

resultin

thedeletionofex

on5

c.157_1

58de

lAT

p.Met53Asnfs*3

5SE

DT

313400

Ged

eonet

al58,59;F

iedleret

al165

c.183_1

84de

lGA

p.Ly

s62Asnfs*2

6SE

DT

313400

Fiedler

etal165

c.191_1

92de

lTG

p.Val64Glyfs*2

4SE

DT

313400

Ged

eonet

al58,59

c.197_3

24+121de

l693

ND

SEDT

313400

Takagie

tal172

693bpdeletionstartingin

exon

4an

den

dingin

intron

5follo

wingthefifthex

on (Con

tinu

es)

SACHER ET AL. 5

TABLE

3(Continue

d)

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

c.239-9_1

2de

lTTAA

ND

SEDT

313400

Ged

eonet

al59;F

iedleret

al165

Predictedsplicevarian

tin

the

intronupstream

ofex

on

5(IV

S4-9_1

2delTTAA)

c.239-4_1

1de

lAATTATTT

ND

SEDT

313400

Ged

eonet

al59

Predictedsplicevarian

tin

the

intronupstream

ofex

on

5(IV

S4-4_1

1delAATTATTT)

c.241_2

42de

lAT

p.Met81Glufs*7

SEDT

313400

Mum

met

al173;G

edeo

net

al59

c.262_2

66de

lGACAT

p.Asp88Ly

sfs*12

SEDT

313400

Ged

eonet

al59

c.267_2

71de

lAAGAC

p.Gln91Argfs*9

SEDT

313400

Mum

met

al174;S

huet

al175;F

iedler

etal176;L

ietal177

c.271_2

75de

lCAAGA

p.Gln91Argfs*9

SEDT

313400

Ged

eonet

al59;F

iedleret

al165

c.272_2

73de

lAA

p.Gln91Argfs*1

0SE

DT

313400

Ged

eonet

al59

c.293de

lTp.Phe

98Se

rfs*10

SEDT

313400

Xiaoet

al178

c.325-4_1

0de

lTCTTTCCinsA

A)

ND

SEDT

313400

Ged

eonet

al59;F

iedleret

al165

Predictedsplicevarian

tin

the

intronupstream

ofex

on

6(IV

S5-4_1

0delTCTTTCCinsA

A)

c.333_3

36de

lGAAT

p.Met111Ile

fs*2

8SE

DT

313400

Shaw

etal179

c.341-11_9

delAAT

ND

SEDT

313400

Daviset

al180

Splicevarian

tthat

resultsin

the

deletionofex

on5

c.384de

lAp.Val130Phe

fs*1

0SE

DT

313400

Bar-Yosefet

al181

Exo

n3de

letion

Absen

tSE

DT

313400

Matsuie

tal182

1763bpdeletionen

compassing

partofex

on3harboringthe

initiatormethioninean

dthe

precedingintron

Exo

n3de

letion

Absen

tSE

DT

313400

Ged

eonet

al59

Thedeletionen

compassesex

on

3harboringtheinitiator

methionine

Exo

n3de

letion

Absen

tSE

DT

313400

Fiedler

etal165

Anunmap

ped

deletion

enco

mpassingex

on3harboring

theinitiatormethionine

Exo

n4-exo

n6de

letion

ND

SEDT

313400

Fiedler

etal165

Alargeunmap

ped

deletion

enco

mpassingex

ons4-6

Exo

n6de

letion

ND

SEDT

313400

Shaw

etal179;G

edeo

net

al59

1335bpdeletionen

compassing

partofex

on6an

dthepreceding

intron

Exo

n6de

letion

ND

SEDT

313400

Christieet

al164

1445bpan

d750bpdeletions

enco

mpassingpartofex

on6an

dtheprecedingintron

6 SACHER ET AL.

TABLE

3(Continue

d)

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

c.322-1_2

delAG

c.322_3

32de

lTTTCAATGAA

p.Asp109_Ser123de

l,Se

r124fs*2

SEDT

313400

Luet

al183;M

aet

al184

13bpdeletionspan

ningthefirst

11bpofex

on6an

dthelast

twobases

ofthepreceding

intronresultingin

theactivation

ofacryp

ticsplicesite

inex

on6;

based

onNM_0

01011658.3

varian

tisp.Phe1

09_Ser123del,

Ser124Cysfs*3

c.-21A>G

ND

SEDT

313400

Ged

eonet

al59;R

uyanie

tal185

Predictedsplicevarian

tin

the

intronupstream

ofex

on

3harboringthefirstco

dingex

on

(IVS2

-2A>G)

c.-21A>C

ND

SEDT

313400

Gao

etal186;L

uoet

al187

Predictedsplicevarian

tin

the

intronupstream

ofex

on3,the

firstco

dingex

on(IV

S2-2A>C)

c.93+1G>A

p.Asp32Ile

fs*2

1SE

DT

313400

Ada

chie

tal188

Splicevarian

tresultingin

the

insertionofATACbetwee

nex

on

3an

dex

on4

c.93+5G>A

Absen

tSE

DT

313400

Ged

eonet

al59;T

iller

etal189;

Fiedler

etal165;R

yuet

al190;

Wan

get

al191;W

uet

al192

Predictedsplicevarian

tpredicted

todeleteex

on3harboringthe

initiatormethionine

(IVS3

+5G>A)

c.237+1A>G

p.His80Profs*1

4SE

DT

313400

Guo

etal193;X

ionget

al194

Splicevarian

tthat

resultsin

the

deletionofthefirstfive

bases

of

exon5(IV

S4+1A>G)

c.237+4T>C

p.His80Thrfs*1

1SE

DT

313400

Shaw

etal179

Splicevarian

tthat

resultsin

exon

4follo

wed

by113bpofthe

subsequen

tintron(IV

S4+4T>C)

c.320_3

21insT

p.Phe

109Valfs*8

SEDT

313400

Ged

eonet

al59

c.325-2A>C

ND

SEDT

313400

Ged

eonet

al59

Predictedsplicevarian

tin

the

intronupstream

ofex

on

6(IV

S5-2A>C)

c.370_3

71insA

p.Se

r124Ly

sfs*4

SEDT

313400

Xiaet

al195

TRAPPC2L

MIM

:610970

c.33+1G>A

c.294+6_9

delTCAG

p.Val69_Ser98de

l;full-leng

thprotein

also

detected

Mild

tomode

rate

deve

lopm

ental

delaywithsomeworsen

ing

follo

wingacuteillne

ss

—P.van

Hasselt(personal

commun

ication)

Compoundheterozygo

us;thefirst

varian

tispredictedto

resultin

deletionofex

on1harboringthe

initiatormethionine,

theseco

nd

resultsin

exon3deletionan

dan

in-framedeletionof30am

ino

acids;inco

mplete

pen

etrance

since

full-lengthwild

-typ

eprotein

isalso

detected

c.109G>T

p.Asp37Tyr

Neu

rode

velopm

entald

elay,feb

rile

illne

ss-ind

uced

enceph

alopa

thy,

—Milevet

al65

(Con

tinu

es)

SACHER ET AL. 7

TABLE

3(Continue

d)

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

rhab

domyo

lysis,de

velopm

ental

arrest,e

pilepsy,tetrap

legia

TRAPPC6A

MIM

:610396

Naturalvarian

tp.Val29_Lys42de

lFoun

din

brainplaq

uesin

norm

alan

dAlzhe

imer'sdiseasepa

tien

ts—

Cha

nget

al71

Naturally

occurringsplicevarian

tthat

lead

sto

inan

in-frame

deletionof14am

inoacids

(TRAPPC6A1orTRAPPC6Δ)

c.319T>A

p.Tyr107Asn

Intellectua

ldisab

ility,spe

echde

lay,

facialdy

smorphism

,polyda

ctyly

Moha

moud

etal78

Oneoffive

rare,h

omozygo

us,

predictedpathoge

nicvarian

tsthat

includevarian

tsin

ANKK1,

RPSH

6A,A

LKBH8an

dAMOTL

1

TRAPPC6B

MIM

:610397

c.82-2A>G

p.Glu28Valfs*1

1Microceph

aly,

epilepsy,au

tistic

features,gen

eralized

wea

kness,

ataxicgait,corticalatroph

y,thin

corpus

callo

sum

—Marin-V

alen

ciaet

al82

Splicevarian

tthat

deletes

exon2

c.124C>T

p.Arg42*

Non-synd

romicau

tosomal

recessiveintellectua

ldisab

ility

(NS-ARID

)

—Harripa

ulet

al81

c.485G>A

p.Arg50Se

rfs*2

Restlesslegs

synd

rome2(RLS

2)

608831

Arido

net

al83

Variantresultsin

exon3skipping,

predictedprotein

isforex

on

2-exo

n4varian

t;au

tosomal

dominan

tinheritan

ce;o

riginal

mutationtake

sinto

acco

untthe

first335bpofuntran

slated

regionan

dtheaffected

baseisc.

G150

TRAPPC9

MIM

:611966

c.1423C>T

p.Arg475*

Seve

reintellectua

ldisab

ility,

microceph

aly,diminishe

dwhite

mattervo

lume,

thinning

ofthe

corpus

callo

sum,red

uced

cerebe

llarvo

lume

613192

Miret

al196;A

bouJamra

etal197;

Moch

idaet

al198;G

iorgio

etal199;

Abb

asie

tal200;H

arripau

letal81

c.2065G>T

p.Glu689*

Seve

reintellectua

ldisab

ility,

microceph

aly,motorde

lay,

absent

spee

ch,corpus

callo

sum

thinning

,red

uced

white

matter

613192

Abb

asie

tal200

c.2311_2

314de

lTGTT

p.Le

u772Trpfs*7

Mode

rate

toseve

remen

tal

retardation/intellectua

ldisab

ility,

borderlin

emicroceph

alyin

some

individu

als,diminishe

dwhite

mattervo

lume,

thinning

ofthe

corpus

callo

sum

613192

Miret

al196

c.1708C>T

p.Arg570*

Men

talretarda

tion,

microceph

aly,

mye

linations

defects

613192

Philip

peet

al201;M

ortreuxet

al202

c.2851-2A>C

p.Thr951Tyrfs*1

7Hyp

otonia,intellectua

ldisab

ility,

diminishe

dwhite

mattervo

lume,

thinning

oftheco

rpus

callo

sum,

613192

Maran

giet

al203

Splicevarian

tthat

resultsin

deletionofex

on18

8 SACHER ET AL.

TABLE

3(Continue

d)

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

head

circum

ferenc

ebe

twee

n2nd

and10th

centile

c.1024+1G>T

p.Arg293Se

rfs*36

p.His294Glyfs*7

Intellectua

ldisab

ility,m

icroceph

aly

613192

Kakar

etal204;A

bbasie

tal200

Splicevarian

tthat

resultsin

deletionofex

on3an

dboth

exons3an

d4

c.1532C>T

p.Thr511Met

Norm

osm

ichy

pogo

nado

tropic

hypo

gona

dism

(nHH)a

ndKallm

annsynd

rome(KS)

613192

Qua

ynoret

al94

InNM_0

31466.7

varian

tis

c.1826C>Tresultingin

p.

Thr609Met;b

igen

icvarian

tthat

co-seg

regateswithPDE3A

c.1477G>A

c.568_5

74de

lTGGCCAC

Exo

n9-16du

plication

p.Trp190Argfs*9

5ND

Thinco

rpus

callo

sum,sev

ere

intellectua

ldisab

ility,w

hite

matterab

norm

alities,dy

smorphic

features

(includ

inghy

pertelorism

,prominen

tna

salb

ridg

e,short

philtrum,large

chee

ks)

613192

Mortreux

etal202

Compoundheterozygo

uswiththe

seco

ndallele

harboringan

in-frameduplicationofex

ons

9-16

c.2134C>T

Exo

n18-19de

letion

p.Arg712*

ND

Microceph

aly,

thin

corpus

callo

sum,

seve

reintellectua

ldisab

ility,

dysm

orphicfeatures

(includ

ing

shortph

iltrum,large

chee

ks)

613192

Mortreux

etal202

Compoundheterozygo

uswiththe

seco

ndallele

harboringan

out-of-fram

edeletionofex

ons

18-19

Exo

n2-9

duplication

ND

Microceph

aly,

thin

corpus

callo

sum,

seve

reintellectua

ldisab

ility,

dysm

orphicfeatures

(includ

ing

shortph

iltrum,large

chee

ks)

613192

Mortreux

etal202

Homozygo

usduplicationofex

ons

2-9

aswellasa61bpinsertion

resultingin

anout-of-fram

epolypep

tide

c.533T>C

p.Le

u178Pro

Cong

enitalmicroceph

aly,seve

reintellectua

ldisab

ility,

hype

rkinesia,h

ypoplasia

ofthe

corpus

callo

sum,m

ildco

lpoceph

aly,

epilepsy

613192

Due

rinc

kxet

al205

Affectedsiblin

gsalso

havea

truncatingp.Arg741*nonsense

varian

tin

theMCPH1,alsofound

inanon-affectedsiblin

g

TRAPPC11

MIM

:614138

c.2938G>A

p.Gly980Arg

LGMD2S,

elev

ated

CK,sco

liosis,

cataracts

615356

Böge

rsha

usen

etal107

c.1287+5G>A

p.Ala372_Ser429de

lMyo

pathy,elev

ated

CK,e

pilepsy,

deve

lopm

entald

elay,ataxia,

cerebralatroph

y,microceph

aly

615356

Böge

rsha

usen

etal107

Splicevarian

tthat

deletes

exon

12resultingin

anin-frame

deletionin

conjunctionwitha

naturally-occurringskippingof

exon11

c.661-1G>T

c.2938G>A

p.Le

u240Alafs*1

0p.Le

u240Valfs*7

p.Gly980Arg

Slightly

redu

cedwhite

matter

volume,

cataracts,elev

ated

CK,

hepa

tomeg

aly,

elev

ated

AST

and

ALT

,steatohe

patitis,co

ngen

ital

muscu

lardy

stroph

y,lordosis

615356

Lian

get

al108

Compoundheterozygo

us;the

intronicvarian

tresultsin

two

splicingvarian

ts

c.1141C>G

c.3310A>G

p.Pro381Ala

p.Thr1104Ala

Hyp

otonia,seizures,m

icroceph

aly,

camptoda

ctyly,

cholestasis,

—Matalong

aet

al112

Compoundheterozygo

us

(Con

tinu

es)

SACHER ET AL. 9

TABLE

3(Continue

d)

Subu

nit,MIM

forprotein

DNAva

rian

t(rep

orted

)Predicted

/rep

orted

protein

chan

gePhe

notype

ordiso

rder

MIM

for

diso

rder

Referen

ceNotes

neph

ropa

thy,

osteo

pathy,N-an

dO-glyco

sylationde

fects(CDG)

c.1893+3A>G

p.Val588Glyfs*1

6Alacrim

a,acha

lasia,scolio

sis,

cerebralatroph

y,myo

pathy,

intellectua

ldisab

ility,gait

abno

rmalities,shortstature

615356

Koeh

leret

al109

Splicevarian

tthat

deletes

exon18

c.2330A>C

c.513_5

16de

lTTTG

p.Gln777Pro

p.Phe

173Tyrfs*1

3ElevatedCK,d

ystroph

icch

ange

s,low

α-dy

stroglycan

,elevatedAST

andALT

,liver

fibrosis,mild

cerebralatroph

y

615356

Fee

etal110

Compoundheterozygo

us

c.851A>C

c.965+5G>T

p.Gln284Pro

p.Ile

278_G

ln351de

lCMD,e

levatedCK,

hypo

glycosylationof

α-dy

stroglycan

,cereb

ralatroph

y,de

velopm

entald

elay

615356

Larsonet

al111

Compoundheterozygo

us;splice

varian

tthat

deletes

exon9an

dthefirst88bases

ofex

on

10resultingin

anin-frame

deletion

c.1192C>T

c.3014C>T

p.Arg398*

p.Pro1005Le

uLG

MD,p

rogressive

proximalmuscle

wea

kness,elev

ated

CK,lactate

dehy

droge

nase

and

α-hy

droxybu

tarate

dehy

droge

nase

615356

Wan

get

al113

Compoundheterozygo

us

c.1287+5G>A

c.3379_3

380insT

p.Ala372_Ser429de

lp.Asp1127Valfs*4

7W

eakn

ess,microceph

aly,co

gnitive

impa

irmen

t,elev

ated

CK,

spasticity,cho

reiform

move

men

ts,cereb

ralatroph

y

615356

C.Jim

enez

Mallebrera

(personal

commun

ication)

Compoundheterozygo

us

c.2389C>T

p.Gln797*

ElevatedCK,w

eakn

ess,spasticity,

dystonia,de

velopm

entald

elay

—S.

Edv

ardson(personal

commun

ication)

Presumed

compoundheterozygo

us

buttheseco

ndpresumed

intronicvarian

thas

yetto

be

determined

c.(1756,2938)G>A

c.100C>T

p.Gly980Arg

p.Arg34*

Delayed

motorde

velopm

ent,calf

hype

rtroph

y,cataracts,elev

ated

CK,LGMD,d

ystroph

icch

ange

s

615356

A.M

anzuran

dF.M

untoni(personal

commun

ication)

Compoundheterozygo

us;

c.1756G>Aisasilentmutation

TRAPPC12

MIM

:614139

c.145de

lGp.Glu49Argfs*1

4Trunc

alhy

potonia,microceph

aly,

appe

ndicular

spasticity,

hypsarrythmia,e

pilepsy,po

nshy

poplasia,p

artialagen

esisof

theco

rpus

callo

sum,b

rain

atroph

y

—Milevet

al124

c.360du

pCc.1880C>T

p.Glu121Argfs*7

p.Ala627Val

Pons

hypo

plasia,age

nesisofthe

corpus

callo

sum,b

rain

atroph

y,spasticqu

adripleg

ia,m

yoclonic

jerks,seizures,spa

sticity,

neuroge

nicblad

der

—Milevet

al124

Compoundheterozygo

us

Abb

reviations:A

LT,alanine

aminotran

sferase;

AST

,aspartate

aminotran

sferase;

CDG,cong

enitaldisorder

ofglycosylation;

CK,creatinekina

se;L

GMD,lim

bgirdle

musculardystrophy;

ND,n

otdetermined

.The

referenc

esequ

encesused

were:

NM_0

01011658.3

(TRAPPC2),NM_0

16209.4

(TRAPPC2L),N

M_0

24108.2

(TRAPPC6A),NM_1

77452.3

(TRAPPC6B),NM_0

31466.7

(TRAPPC9),NM_0

21942.5

(TRAPPC11)an

dNM_0

16030.5

(TRAPPC12);allv

ariantsareho

mozygo

usun

less

otherwiseno

ted;

allv

ariantsarerecessiveun

less

otherwiseno

ted;

inmost

cases,varian

tsarelistedas

reported

intheprimaryreference

exceptforvari-

ants

repo

rted

asIVSan

dno

n-HGVSno

men

claturevarian

ts,w

hich

have

been

conv

ertedto

HGVSno

men

clature;

protein

varian

tswereve

rified

usingMutationTaster2

06an

dan

ydiscrep

ancies

withthepublished

pap

erreferto

theMutationT

astervarian

t.

10 SACHER ET AL.

physically interacts directly or indirectly with several core TRAPP pro-

teins including TRAPPC3, TRAPPC4 and TRAPPC5, as well as with

complex-specific proteins including TRAPPC8, TRAPPC9, TRAPPC10,

TRAPPC11 and TRAPPC12.17,25,43,57 Localization studies have

reported nuclear, ER-to-Golgi intermediate compartment (ERGIC)

and/or Golgi localization for TRAPPC2, consistent with its functions

as both a transcription regulator and a membrane trafficking

protein.27,51,54

TRAPPC2 was implicated in the skeletal disorder spondyloepiphy-

seal dysplasia tarda (SEDT; also called SEDL) in 1999 when three indi-

viduals with clinical features of SEDT were found to harbor variants in

the TRAPPC2 gene.58 SEDT encompasses several characteristic fea-

tures that include short stature, flattening of the vertebrae with char-

acteristic humps and dysplasia of the ends of large bones. The

affected individuals in the original report all had dinucleotide deletions

resulting in frameshifts and premature truncation of the 140 amino

acid protein (Table 3). Subsequent studies identified five missense

variants.59–62 All but one of these variants (c.139G>T, p.Asp47Tyr)

are predicted to affect the overall fold of the protein.48,63 Interest-

ingly, Asp47 is not involved in any known interactions with core

TRAPP proteins25 and this residue has been shown to be required for

its interaction with other TRAPP complex-specific proteins in both

yeast and higher eukaryotes.41,43 The remaining variants either affect

splicing or cause frameshifts within the open reading frame, both

resulting in truncations of this relatively small protein.

To date, all individuals with TRAPPC2 variants suffer from SEDT.

However, no other TRAPP gene variant has been linked to SEDT or

any similar type of skeletal defect. These facts suggest that either

TRAPPC2 has a unique role within TRAPP complexes, or variants in

this small protein affect a non-TRAPP function of TRAPPC2. As depo-

sition of collagen is required for bone development, the specific role

of TRAPPC2 in collagen trafficking (discussed above) is a likely expla-

nation for its role in SEDT.

3.2 | TRAPPC2L (MIM 610970)

The TRAPPC2L protein was initially identified using a bioinformatics

approach as a protein related to TRAPPC2.57 A multiple sequence

alignment demonstrated that only two residues are conserved

between these two proteins—Leu36 and Asp37 (TRAPPC2L number-

ing). Using tandem affinity purification-tagged TRAPPC2L and

TRAPPC2, it was shown that both of these proteins are components

of the same TRAPP complex(es). Although the three-dimensional

structure of TRAPPC2L is yet to be solved, it can be modeled on its

yeast homologue called Tca1764 (Figure 2). Consistent with its primary

structural similarities to TRAPPC2 and its yeast homologue Trs20,

Tca17 also adopts a longin-domain fold composed of a central five-

stranded β-sheet flanked by three α-helices. The only two residues

conserved between TRAPPC2L and TRAPPC2 are predicted to be

exposed at the surface of TRAPPC2L, suggesting it too may act as an

adaptor protein for other TRAPP subunits, a notion that appears to be

supported (see below).

A portion of some TRAPP proteins co-fractionated with

TRAPPC2L on membranes of relatively low density on a density gradi-

ent while a second pool was found to fractionate at a higher density.57

While the denser membranes co-fractionated with Golgi markers, the

lighter membrane fraction containing TRAPPC2L partially overlapped

with a marker for early endosomes, suggesting that TRAPP complexes

containing TRAPPC2L may function in a post-Golgi compartment.

Recently, individuals were identified with homozygous variants in

TRAPPC2L.65 Interestingly, the individuals were found to have a mis-

sense variant of the conserved Asp37 residue (p.Asp37Tyr). As stated

above, the identical variant in TRAPPC2 results in the skeletal defect

SEDT. In contrast, the TRAPPC2L individuals harboring this variant

suffer from a global developmental delay, microcephaly, dystonia, tet-

raplegia, rhabdomyolysis, encephalopathy and epilepsy. The p.

Asp37Tyr variant and the equivalent yeast variant (Tca17 Asp45Tyr)

both interfere with the interaction between TRAPPC2L and

TRAPPC10 (Trs130 in yeast). Although a TRAPPC2L knockdown in

HeLa cells results in a fragmentation of the Golgi,57 fibroblasts derived

from the individuals with TRAPPC2L variants did not display an

abnormal Golgi morphology.65 These fibroblasts had defects in the

trafficking of Golgi marker proteins and also displayed a defect in the

exit of a marker protein from the Golgi. Interestingly, GFP-tagged

FIGURE 2 The location of the conserved leucine and aspartic acid

residues on TRAPPC2 and TRAPPC2L. A, TRAPPC2L was modeledusing the structure of its yeast homologue Tca17 (PDB ID: 3PR6). Thehighly similar structure of TRAPPC2 (PDB ID: 1H3Q) is shown on theright for comparison. The location of alpha helix α1, where the onlytwo conserved residues between the two proteins are found, isindicated. B, A close-up view of the overlay of helices α1 fromTRAPPC2L and TRAPPC2 with the conserved leucine and asparticacid residues is shown. The side chains are oriented similarly. Note

that helix α1 is not involved in the interaction between TRAPPC2 andother TRAPP subunits of the core complex. The ribbons are colored asin panel A

SACHER ET AL. 11

Rab11 localization was altered, with larger and/or more abundant

GFP-Rab11 punctae. In addition, there was an increased level of the

active (GTP-bound) form of Rab11. This suggests that TRAPPC2L

either negatively regulates the GEF activity of TRAPP for Rab11, or it

participates in the recruitment of a Rab11 GAP. The recruitment of a

GAP by a TRAPP complex was recently demonstrated in yeast.66 As

Rab11 has been implicated in trafficking at recycling endosomes,67

the earlier finding that TRAPPC2L fractionates with light membranes

that may also contain the endosomal marker EEA1 is consistent with

TRAPPC2L and Rab11 functioning on the same membranes. It is note-

worthy that the yeast TRAPP II complex (that contains the TRAPPC2L

homologue Tca17) was recently demonstrated to facilitate nucleotide

exchange on the yeast Rab11 homologues Ypt31 and Ypt32,24 further

strengthening the connection between TRAPPC2L and Rab11. It

should be noted that a formal demonstration of the involvement of a

human TRAPPC2L-containing TRAPP complex acting as a GEF for

Rab11 has yet to be shown. Given the large number of effector pro-

teins for Rab11,68 it remains to be seen how overactivation of this

GTPase results in the clinical pathology of these individuals. As a

potential clue, a defect in ciliogenesis and cilia length was noted in the

fibroblasts from these individuals, consistent with the link between

TRAPP, Rab11 and cilia.69

3.3 | TRAPPC6A (MIM 610396)

Three isoforms of the TRAPPC6 protein have been described in

humans. These include TRAPPC6A1, TRAPPC6A2 and TRAPPC6B.70

TRAPPC6A1 and TRAPPC6B are encoded by different genes and

share 56% identity and 72% similarity, while TRAPPC6A2 contains an

additional, internal 14 amino acid stretch compared to TRAPPC6A1.

In light of this difference, TRAPPC6A1 has also been referred to in

more recent literature as TRAPPC6AΔ.71,72 In yeast, the TRAPPC6

homologue Trs33 has been implicated in assembly of the TRAPP II

complex via an interaction with the TRAPP II-specific subunit

Trs120.36

TRAPPC6A was implicated in pigmentation in a mosaic hypopig-

mentation (mhyp) mouse in which a provirus randomly inserted into

the intron immediately following exon 1 of the gene.73 The authors

suggested that TRAPPC6A is involved in the biogenesis of melano-

somes. It is noteworthy that the expression of the TRAPPC6A gene

was nearly completely turned off in this mouse. Given that the gene

likely shares a promoter in a head-to-head fashion with its neighbor-

ing gene BLOC1S3 whose product is implicated in melanosome bio-

genesis and hypopigmentation,74 reduced expression of BLOC1S3

would also be expected in the mhyp mouse calling into question the

role of TRAPPC6A in pigmentation.

The crystal structure of TRAPPC6A1 was solved in a heterodi-

meric complex with its TRAPP binding partner TRAPPC3.75 Remark-

ably, although these two proteins share little sequence identity, the

overall folds of the two proteins were strikingly similar with both pro-

teins composed of a mixed α/β-fold containing four α-helices and four

β-strands forming an antiparallel β-sheet. One notable difference

between these proteins is the absence of a hydrophobic tunnel in

TRAPPC6A1 that was seen in the TRAPPC3 crystal structure.76

TRAPPC6A1 was recently found in extracellular plaques from the

brain cortex of individuals with Alzheimer's disease (AD).71 These pla-

ques were also reactive with an antibody that recognizes

Ser35-phosphorylated TRAPPC6A1. Although it is unclear how this

otherwise cytosolic protein would be released from cells, the authors

propose a mechanism for aggregation of TRAPPC6A1. WWOX, a

tumor suppressor, prevents aggregation of TRAPPC6A1. When

WWOX is downregulated, as it is in AD individuals, TRAPPC6A1 is

phosphorylated at Ser35, aggregates and induces caspase 3 activation,

which has been proposed to contribute to the production of the path-

ogenic Aβ peptide.77 TRAPPC6A1 would then serve as a platform for

Aβ plaque formation. A subsequent report demonstrated that zinc

finger-like protein that regulates apoptosis (Zfra), a naturally occurring

31 amino acid peptide, reduced phosphorylation of TRAPPC6A1 and

prevented its deposition in cortical plaques.72 It remains unclear what

role TRAPPC6A1 plays in the etiology of AD. A TRAPPC6A2 missense

variant was recently reported in individuals with a clinical spectrum

including intellectual deficit, speech delay, polydactyly and facial dys-

morphism.78 The variant was one of five homozygous variants

detected in these individuals, all of which are rare and predicted to be

pathogenic. While some of the clinical features are similar to those of

individuals harboring other TRAPP gene variants (see Table 3), it is

unclear if the clinical features in these individuals are due to the

TRAPPC6A2 variant, one of the other variants or some combination

of the five variants.

3.4 | TRAPPC6B (MIM 610397)

The structure of TRAPPC6B was solved both as a homodimer79 and a

heterodimer in a complex with TRAPPC3.80 Not unexpectedly, the

TRAPPC6A1-TRAPPC3 and TRAPPC6B-TRAPPC3 heterodimers are

nearly the same, although the TRAPPC6A1-containing heterodimer

occupies a larger surface area of TRAPPC3 than does the one contain-

ing TRAPPC6B. A small stretch of non-conserved amino acids maps to

the surface of each heterodimer, suggesting that the heterodimers

may interact with different proteins although tissue-specific expres-

sion was not seen for either of the isoforms in mouse tissue.80 Both

heterodimers formed a heterotrimeric complex with TRAPPC1,25,80

suggesting they can interact with other TRAPP proteins to form iso-

complexes. Proof of such isocomplexes was demonstrated by immu-

noprecipitation studies in mammalian cells.70

Variants in TRAPPC6B were recently reported. In one study

aimed at identifying genetic variants contributing to non-syndromic

autosomal recessive intellectual disability (NS-ARID) in 192 consan-

guineous Iranian and Pakistani families, a truncating variant in

TRAPPC6B was reported.81 The same study also identified a truncat-

ing variant in the TRAPP gene encoding TRAPPC9 in another family.

This is of interest given the interaction between the yeast homo-

logues for TRAPPC6 and TRAPPC9 (Trs33 and Trs120, respectively;

see above). A second report identified TRAPPC6B splice variants in six

individuals from three unrelated consanguineous families of Egyptian

origin.82 All affected individuals had similar phenotypes that included

microcephaly, epilepsy and brain malformations including atrophy and

thinning of the corpus callosum. These phenotypes are similar to

those of individuals with TRAPPC9 variants (Table 3) and may result

12 SACHER ET AL.

from an impaired association of TRAPPC9 with TRAPP II. A third

study identified a heterozygous TRAPPC6B variant in an individual

with restless legs syndrome 2.83 Fourteen other variants were

excluded due to either high frequency in the population or mild pre-

dicted effect. The resulting protein (p.Arg50Serfs*2) represents a

severe truncation and is presumed autosomal dominant by the

authors. If TRAPPC6B interacts with TRAPPC9, there might be an

expectation of a TRAPPC9-related phenotype (eg, microcephaly, intel-

lectual disability). However, no such phenotype was reported. This

would suggest that either there are sufficient TRAPPC9-containing

TRAPP complexes remaining or the truncated protein may still inter-

act with TRAPPC9 but not with some other, perhaps non-TRAPP,

protein.

3.5 | TRAPPC9 (MIM 611966)

Following the discovery of Trs120 in yeast as a component of TRAPP

II,13,15 TRAPPC9, its human homologue, was detected in immunopre-

cipitates employing tagged versions of TRAPPC3,70 TRAPPC217,43

and TRAPPC2L,17 as well as in a high-molecular-weight complex.27

TRAPPC9 is thought to be a component of a TRAPPC10-containing

complex.18 However, while TRAPPC9 was implicated in ER-derived

COP II vesicle dynamics,84 TRAPPC10 depletion did not affect this

membrane trafficking step.27 A TRAPPC9-containing complex bound

to Rab18 in its nucleotide-free form and was shown to have GEF

activity for this Rab.28 The authors further demonstrated that deletion

of either TRAPPC9 or both TRAPPC9 and TRAPPC10 did not affect

membrane traffic but resulted in the appearance of lipid droplets.

TRAPPC9 (called NIBP) was detected in a yeast two-hybrid screen as

an interacting partner of the signaling kinase NIK, and was also found

to interact with the β-subunit of the kinase IKK (IKKβ),85 both of

which function in the Nuclear Factor - kappa B (NF-κB) signaling path-

way. Subsequently, a number of studies have implicated TRAPPC9/

NIBP in NF-κB signaling, with a possible role in cancer

metastasis.86–89

Although the structure of TRAPPC9 is not known, several studies

have addressed aspects of its structure. The amino-terminal portion of

the protein (amino acids 117-411) is predicted to adopt an α-solenoid

structure with multiple tetratricopeptide repeat (TPR) domains.90 Such

repeats are known to be involved in protein-protein interactions.91

The carboxy portion of the protein is predicted to contain two ASPM,

SPD-2, Hydin (ASH) domains,90 believed to target proteins to the cil-

ium.92 A computational model of TRAPPC9 was built using a con-

served metalloprotein from Bacillus cereus.93 Although largely helical,

which would be consistent with the predicted TPR and ASH domains,

the modeled structure was not reported to have these domains.

A number of variants in TRAPPC9 have now been reported

(Table 3). With the exception of a single report where the affected

individual had bigenic TRAPPC9 and PDE3A variants,94 all individuals

with biallelic variants in TRAPPC9 have a strikingly common pathology.

These individuals all display NS-ARID and postnatal microcephaly.

Most are reported to have minimal to no speech and behavioral prob-

lems. Some individuals also display abnormalities in the brain such as

thinning of the corpus callosum, reduced white matter volume and

myelination defects. In addition to these individuals, an individual with

a larger homozygous deletion on chromosome 8 encompassing only

the TRAPPC9/NIBP gene was reported, with a phenotype similar to

those with TRAPPC9 variants.95 Another individual, identified by

homozygosity mapping, had a form of autosomal recessive mental

retardation that mapped to the TRAPPC9 gene on chromosome 8.96

Although a number of genes have been linked to NS-ARID,97

TRAPPC9 is unique in that it is the only gene that has been linked to

this disorder in more than five families.93,97 There are several reasons

that support the notion that dysregulation of the NF-κB pathway may

be a contributing factor in the pathology of individuals with TRAPPC9

variants. First, there is a growing amount of literature on the involve-

ment of TRAPPC9 in the NF-κB signaling pathway.85–89,98 Second,

this pathway is documented to be important for brain function and

development.99,100 Third, while TRAPPC9 is expressed in a variety of

tissues, with the highest being muscle, there is a significant level of

the transcript in brain.85 Fourth, another gene implicated in NS-ARID

also impacts NF- κB signaling.101 Thus, it is tempting to speculate that

variants in TRAPPC9 affect the NF-κB pathway leading to NS-ARID.

However, as detailed below, variants in other TRAPP proteins share

some of these clinical features, particularly intellectual disability, brain

abnormalities and microcephaly. It is possible that there is a wide

range of levels of intellectual disability in individuals with TRAPP gene

variants and, indeed, there is a rather large spectrum of intellectual

disabilities in general. As one of the striking features of TRAPPC9

depletion is an increase in lipid droplet formation,28 it is unclear how

this links to NF-κB signaling and intellectual disability.

3.6 | TRAPPC11 (MIM 614138)

In an effort to address whether TRAPPC2 and TRAPPC2L associate

with different components of TRAPP, each was appended to a tan-

dem affinity purification tag and purified from HeLa cell lysates.17 In

addition to identifying proteins that were homologous to known yeast

TRAPP subunits (see Table 2), several additional proteins were identi-

fied. One of these proteins was called TRAPPC11 (also called

c4orf41). The protein is 1133 amino acids in length and does not have

a recognizable homologue in the yeasts S. cerevisiae and Schizosac-

charomyces pombe but is found in metazoans. Like other TRAPP-

associated proteins, depletion of the protein by RNA interference

resulted in a fragmented Golgi.17 In addition, depletion of the protein

arrested a marker protein that normally traverses the secretory path-

way in a pre-Golgi compartment that was suggested to be either the

ERGIC or ER exit sites. The latter result is consistent with a recent

study that suggested a role for TRAPPC12, a protein found in the

same TRAPP complex as TRAPPC11, in recruitment of the outer layer

of the COP II coat to the ER.19 In another study employing a different

marker protein, ER exit was unaffected and the marker protein was

arrested in the Golgi,102 suggesting TRAPPC11 may function in more

than one step of membrane trafficking. Depletion of the Drosophila

melanogaster TRAPPC11 homologue, called gryzun,103 was shown to

alter the localization of a cell-surface marker, suggesting a defect in

Golgi function.102 The Danio rerio homologue of TRAPPC11 was found

in a zebrafish genetic screen aiming to identify genes involved in liver

disease.104 Indeed, owing to the hepatomegaly seen in the zebrafish

TRAPPC11 mutant, the gene was referred to as foie gras (fgr). Closer

SACHER ET AL. 13

inspection revealed that the livers in the fgr mutant zebrafish accumu-

lated a substantial amount of lipids.

Although the three-dimensional structure of TRAPPC11 has not

been solved, the protein has a region of high conservation that has

been referred to as the foie gras domain. Bioinformatic analysis

reveals that this domain harbors several regions that may assume a

TPR structure. In addition, the protein also has a carboxy-terminal gry-

zun domain whose function remains unknown.

A recent study implicated human and zebrafish TRAPPC11, to the

exclusion of other TRAPP proteins, in N-linked glycosylation.105 The

trappc11 mutant zebrafish had an upregulated unfolded protein

response (UPR). Although protein secretion was defective in the

trappc11 mutant zebrafish, this could not explain the upregulated

UPR because blocking secretion by other means did not result in a

similar UPR. Instead, the trappc11 mutant zebrafish phenocopied

tunicamycin-treated fish. Tunicamycin inhibits N-linked glycosylation

by reducing the levels of lipid-linked oligosaccharides. This was also

found to be the case in the trappc11 mutant fish and, unexpectedly,

genes involved in the synthesis of dolichol (the lipid carrier of the car-

bohydrates) were upregulated in these zebrafish. Because blocking N-

linked glycosylation by tunicamycin treatment of zebrafish results in

fatty liver and an upregulation of the UPR,106 the authors concluded

that fatty liver in the trappc11 mutant zebrafish is induced by a similar

mechanism. Strikingly, in HeLa cells, hypoglycosylation of a resident

ER protein was reported upon depletion of TRAPPC11, but not upon

depletion of any other TRAPP proteins tested. These results suggest

that either TRAPPC11 functions outside of the TRAPP complex or

binds to some factor that is important for lipid-linked oligosaccharide

synthesis while still within the TRAPP III complex.

The first individuals with TRAPPC11 variants were reported in

2013107 (Table 3). The individuals had homozygous variants resulting

in a missense variant (p.Gly980Arg) or a deletion of a portion of the

foie gras domain (p.Ala372_Ser429del). The former variant was associ-

ated with a limb girdle muscular dystrophy 2S (LGMD2S) and cata-

racts in one individual, while the latter was associated with myopathy,

intellectual deficit, hyperkinetic movements and ataxia. A subsequent

report described another TRAPPC11 variant in which the phenotype

was composed of congenital muscular dystrophy (CMD), hepatic stea-

tosis and cataracts.108 In 2017, Koehler et al identified individuals

with TRAPPC11 variants that also suffered from CMD and further

broadened the phenotype to include achalasia, alacrima and scolio-

sis.109 Siblings with compound heterozygous TRAPPC11 variants (p.

Gln777Pro and p.Phe173Tyrfs13*) and a phenotype similar to those

reported by Liang et al108 were recently reported.110 In addition to

CMD, these latter individuals were also observed to have abnormal

dystroglycan staining. The first documented case of a TRAPPC11 vari-

ant resulting in an α-dystroglycanopathy was recently reported.111

This individual also had liver, eye and brain pathology. Matalonga

et al reported an individual with a TRAPPC11 variant that resulted in

N- and O-linked glycosylation defects reminiscent of a congenital dis-

order of glycosylation, with hypotonia but no myopathic changes, and

brain atrophy.112 Several other individuals with confirmed variants in

TRAPPC11 have been identified but yet to be reported in the litera-

ture (Table 3). The phenotypes of these individuals resemble those of

most other TRAPPC11 variants including LGMD, weakness and

cognitive impairment. When reported, creatine kinase (CK) levels were

elevated in individuals with TRAPPC11 variants, further indicative of a

muscle pathology.107,108,110,111 A recent case report described individ-

uals with a compound heterozygous variant in TRAPPC11 who only

present with LGMD2S but none of the other neuromuscular, ocular or

hepatic phenotypes found in other individuals.113 Analysis of all

known TRAPPC11 variants indicates residues and regions of the pro-

tein that are important for function (Figure 3). These include the foie

gras domain and residues near it, Gly980 and the extreme carboxy-

terminus of the protein.

Collectively, variants in TRAPPC11 appear to affect muscle, eye,

brain and to some extent liver. Muscle and brain involvement (in the

form of cognitive impairment), and to a lesser degree eye defects, are

commonly seen in forms of muscular dystrophy, particularly when

caused by variants in either α-dystroglycan (αDG) or genes required

for its proper glycosylation.114 This is due to the fact that the unique

O-linked glycans on αDG are responsible for interactions with the

extracellular matrix (ECM).115 Thus, it is significant that αDG changes

were reported in two individuals with TRAPPC11 variants110,111

because the phenotypes of many of the TRAPPC11 individuals are

similar to those of individuals with dystroglycanopathy. How

TRAPPC11 might be involved in the muscular phenotypes is not clear

and several possibilities can be envisioned. First, given its recently

reported role in the production of lipid-linked oligosaccharides,105

necessary for both N- and O-linked glycosylation, defects in

TRAPPC11 may inhibit the proper glycosylation of αDG by reducing

levels of dolichol-linked carbohydrates, thus preventing αDG from

forming stable interactions with the ECM. Second, given its role in

membrane traffic, particularly at the level of the Golgi, TRAPPC11 var-

iants may alter the trafficking and localization of several key Golgi

enzymes necessary for the unique glycans that enable αDG to interact

with the ECM. Such enzymes include POMT1 and 2, LARGE1 and

2, and POMGNT2 to name a few.116 Finally, TRAPPC11 has been

implicated in autophagy44 (D. Stanga and M. Sacher, unpublished

data), and this process is involved in several forms of muscular dystro-

phy.117 Thus, with TRAPPC11 functioning in several different cellular

FIGURE 3 Schematic of the location of all known TRAPPC11

variants. A cartoon of TRAPPC11 indicating the foie gras (amino acids263-521) and gryzun (amino acids 1036-1095) domains is shown.Variants listed in black and bold represent homozygous variants. Notethat Q797* is a presumed compound heterozygous variant but thesecond variant is unknown. Compound heterozygous variants aredepicted in the same color and the same level away from the cartoon.Most variants fall within and near the foie gras domain and near thecarboxy-terminus, suggesting important functions for these regions ofthe protein

14 SACHER ET AL.

processes, identifying how it results in muscle, eye and brain patholo-

gies will require further dissection of its functions and the use of alter-

native model systems to study muscle biology.

3.7 | TRAPPC12 (MIM: 617669)

Another complex-specific protein is TRAPPC12 (also known as

TTC15, TRAMM and CGI-87). This protein is found in metazoa but

does not have a recognizable homologue in yeast. It was first identi-

fied in a human autophagy proteomic study44 and subsequently char-

acterized as a component of the human TRAPP complex.17 It was

suggested to be a component of the human TRAPP III complex by vir-

tue of its co-purification with TRAPPC8, but not with TRAPPC9 or

TRAPPC1018 (see Figure 1).

Although the structure of TRAPPC12 is yet to be solved, the pri-

mary protein sequence indicates the existence of four conserved TPR

motifs localized close to its carboxy-terminus that likely facilitate its

interaction with other proteins.91 Within the amino-terminal ~200

amino acids there is a region that was shown to be

phosphorylated,118–120 and some of these phosphoresidues appear to

regulate the function of the protein.121

Immunofluorescence experiments revealed that the protein is dis-

tributed as punctae mainly in the cytoplasm and on ER exit sites, and

partially co-localizes with the Golgi.17,19,121 Furthermore, traces of the

stained protein were also visible in the nucleus, a finding confirmed by

subcellular fractionation, biochemical techniques and fluorescence

microscopy.121

The TRAPPC12 protein was demonstrated to be involved in ER-

to-Golgi transport, the regulation of Golgi integrity and autop-

hagy.17,44,122 More recently, a function for the protein in mitosis was

also revealed.121 Depletion of TRAPPC12, but not of any other

TRAPP-associated protein, resulted in a significant increase in the

mitotic index due to a defect in chromosome congression and activa-

tion of the spindle assembly checkpoint. TRAPPC12 associated with

metaphase chromosomes and weakly localized to their kinetochores

where it was shown to be involved in the recruitment of several kinet-

ochore proteins, most dramatically that of CENP-E. Size exclusion

chromatography demonstrated that during mitosis TRAPPC12 was

phosphorylated and no longer co-fractionated with the TRAPP com-

plex. The role of TRAPPC12 in mitosis is likely conserved because an

association of chicken TRAPPC12 with mitotic chromosomes was also

reported.123

Recently, three individuals from two unrelated families harboring

two different TRAPPC12 variants were reported.124 One of them has

a homozygous truncating variant (p.Glu49Argfs*14) resulting in the

absence of full-length protein. The other two individuals are siblings

that harbor two compound heterozygous variants (p.Glu121Argfs*7

and p.Ala627Val). These variants also result in an absence of full-

length protein, suggesting that the missense p.Ala627Val variant in

one of the TPR motifs destabilizes the protein. Importantly, all three

individuals displayed similar clinical phenotypes including global devel-

opmental delay, severe disability, microcephaly, hearing loss, spastic-

ity, brain atrophy and encephalopathy. Similar to HeLa cells depleted

of TRAPPC12,17,121 fibroblasts derived from all three individuals

showed a fragmented Golgi that was rescued by expression of wild-

type TRAPPC12,124 confirming that the phenotype was due to dys-

functional TRAPPC12. Cargo transport from the ER to and through

the Golgi was delayed. In addition, a delay in mitosis was also

observed in fibroblasts from all three individuals. These results are

consistent with the reported functions of TRAPPC12 in membrane

traffic and mitosis.17,121 While a defect in mitosis cannot be ruled out

as a contributing factor in the clinical pathology, given the overlapping

phenotypes with other TRAPP variants, at least part of the pathology

is likely due to a membrane trafficking defect.

4 | TRAPPOPATHIES: CONVERGENCE ANDDIVERGENCE OF PHENOTYPES

Causality in genetics is often difficult to assign. It is generally

accepted, however, that co-segregation of a phenotype with variants

in a particular gene, and/or studies using a wild-type protein to cor-

rect a cellular phenotype in cells derived from affected individuals

allows causality to be suggested.125,126 The more individuals showing

such co-segregation the stronger the suggestion of causality. With

this in mind, the only other multisubunit tethering factor in which vari-

ants in a large number of subunits have been linked to human disease

is the conserved oligomeric Golgi (COG) complex (Table 4). This com-

plex is composed of eight subunits termed COG1-COG8 that are

organized into two “lobes”: lobe A composed of COG1-COG4 and

lobe B composed of COG5-COG8.127 Variants in seven of the eight

genes that encode these subunits all result in some form of congenital

disorder of glycosylation (CDG), suggesting that impairment of COG

subunits results in impairment of the function of the entire complex.

In contrast, variants in the genes encoding TRAPP proteins result

in phenotypes that, in some cases, are protein-specific. While all vari-

ants in TRAPPC2 are associated with the skeletal defect SEDT, no

other TRAPP gene variant results in a similar skeletal defect, nor have

there been any reports of TRAPPC2 variants associated with any other

phenotype. This suggests that impairment of TRAPPC2 function does

not necessarily affect TRAPP complex function but rather impacts a

TRAPPC2-specific function. As this protein has been implicated in

both regulating the cycling of the GTPase Sar154 and in a nuclear-

specific function,50,52 a function outside of the confines of TRAPP

complexes can be envisioned, perhaps resulting in the unique clinical

pathology.

Variants in TRAPPC11 are linked to muscular disorders including

LGMD2S, CMD and generalized myopathy. This is supported by the

elevated levels of CK in these individuals. In addition, cataracts and

liver involvement have also been reported in some of these individ-

uals. All of the above phenotypes are TRAPPC11-specific. A link

between muscular defects and eye involvement is known, particularly

for dystroglycanopathies.114 Regarding the liver pathology, it has been

shown that TRAPPC11 is involved in lipid-linked oligosaccharide syn-

thesis and upregulation of the UPR.105 This function of TRAPPC11 is

unique and was not observed for other components of the TRAPP

complex. The TRAPPC11-induced UPR includes upregulation of the

transcription factor ATF6, overexpression of which is known to result

in fatty liver.128 Thus, some of the clinical manifestations of

TRAPPC11 variants can be attributed to this unique function of

SACHER ET AL. 15

TRAPPC11. Other phenotypes reported for individuals with variants

in TRAPPC11 include developmental delay, intellectual disability and

in one case microcephaly. Such phenotypes are observed in individ-

uals with variants in other TRAPP-encoding genes including TRAPPC9,

TRAPPC2L and TRAPPC6 (see Table 3), and may be related to the func-

tion of TRAPPC11 within the TRAPP complex and its role in mem-

brane traffic.

TRAPPC9 represents another group with a large number of var-

iants. In essentially all cases, individuals suffer from mental retarda-

tion, microcephaly and brain abnormalities. With the exception of

one individual with a TRAPPC6B variant who displays restless legs

syndrome, the other individuals with TRAPPC6B variants also share

common phenotypes with TRAPPC9 variants. The physical associa-

tion between the yeast counterparts for these gene products

(Trs33 and Trs120) may explain the common pathology. In addition,

recently described individuals with variants in TRAPPC2L also dis-

play developmental delay, microcephaly and brain abnormalities.

The yeast (Tca17) and human proteins both interact with

TRAPPC10 (Trs130 in yeast), a component of the

TRAPPC9-containing human and yeast TRAPP complexes. Thus, a

common set of clinical features in individuals with variants in any

of the aforementioned genes could be explained by a general

impairment of TRAPP II function.

The main phenotypes observed in individuals with TRAPPC12 var-

iants are encephalopathy and microcephaly. Although TRAPPC12 is

unique amongst other TRAPP proteins with a role in mitosis through

the kinetochore protein CENP-E,121 and CENP-E variants also result

in microcephaly,129 given the overlap with clinical phenotypes seen

for other TRAPP variants, it is likely that the clinical features of indi-

viduals with TRAPPC12 variants are also linked to its role within

TRAPP.

5 | CONCLUSION

The burgeoning class of TRAPP-related disorders called TRAPPopa-

thies will undoubtedly expand as whole exome sequencing continues

to rise to prominence as a first-line diagnostic for new clinical disor-

ders. As features of TRAPPopathies continue to be revealed, TRAPP

genes will also start to be included in panel-specific sequencing as is

commonly done for a number of disorders including muscular dystro-

phies. Indeed, given the common muscular phenotype in individuals

with TRAPPC11 variants, it was recently suggested that TRAPPC11 be

included in muscular dystrophy gene panels.111 Understanding the

common clinical features as well as the clinical differences will be an

important goal in guiding clinicians toward treatments and researchers

toward therapeutic targets and possible interventions.

ACKNOWLEDGMENTS

Work in the Sacher laboratory is supported by grants from the Cana-

dian Institutes of Health Research, the Natural Sciences and Engineer-

ing Research Council of Canada and Concordia University. We are

grateful to laboratory members and to Drs Steven Moore, Claudio

Graziano and Alisa Piekny for critical comments and helpful discus-

sions on this work. We also thank all of the clinicians and geneticists

with whom we have collaborated for their input and for allowing the

inclusion of unpublished TRAPP variants. The assistance of Dr Peter

Pawelek in the preparation of Figure 2 is gratefully acknowledged.

We apologize to all authors whose papers could not be cited in this

review due to space limitations.

Editorial Process File

The Editorial Process File is available in the online version of this

article.

TABLE 4 Diseases associated with non-TRAPP multisubunit tethering factors

Multisubunit tethering factor Subunit Disease/OMIM# References

COG COG1 CDG2G/611209 Foulquier et al207; Zeevaert et al208

COG2 CDG2Q/617395 Kodera et al209

COG4 CDG2J/613489 Miura et al210; Reynders et al211; Ng et al212

COG5 CDG2I/613612 Paesold-Burda et al213

COG6 CDG2L/614576 Lubbehusen et al214; Huybrechts215

COG7 CDG2E/608779 Wu et al216; Spaapen et al217; Ng et al218; Moravaet al219; Zeevaert et al220

COG8 CDG2H/611182 Foulquier et al221; Kranz et al222

GARP/EARP VPS53 PCH2E/615851 Ben-Zeev et al223; Feinstein et al224

HOPS/CORVET VPS11 HLD12/616683 Edvardson et al225; Zhang et al226

VPS33A MPSPS/617303 Dursun et al227; Kondo et al228

CHEVI VPS33B ARCS1/208085 Gissen et al229,230; Taha et al231; Smith et al146

VIPAR ARCS2/613404 Cullinane et al232

Exocyst EXOC8 JBTS1/213300 Dixon-Salazar et al233

Dsl1 NAG/NBAS SOPH/614800 Maksimova et al234

NAG/NBAS ILFS2/616483 Haack et al235

Abbreviations: ARCS, arthrogryposis, renal dysfunction and cholestasis; CDG, congenital disorder of glycosylation; HLD, hypomyelinating leukodystrophy;ILFS, infantile liver failure syndrome; JBTS, Joubert syndrome; MPSPS, mucopolysaccharidosis-plus syndrome; PCH, pontocerebellar hypoplasia; SOPH,short stature, optic nerve atrophy and Pelger-Huet anomaly.

16 SACHER ET AL.

ORCID

Michael Sacher http://orcid.org/0000-0003-2926-5064

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How to cite this article: Sacher M, Shahrzad N, Kamel H,

Milev MP. TRAPPopathies: An emerging set of disorders

linked to variations in the genes encoding transport protein

particle (TRAPP)-associated proteins. Traffic. 2018;1–22.

https://doi.org/10.1111/tra.12615

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