PORPHYRIAS...Cutaneous Porphyrias Porph26 PORPHYRIAS CLINICAL MANIFESTATIONS SUNLIGHT-INDUCED SKIN...
Transcript of PORPHYRIAS...Cutaneous Porphyrias Porph26 PORPHYRIAS CLINICAL MANIFESTATIONS SUNLIGHT-INDUCED SKIN...
PORPHYRIAS(Vampires and Crazy Kings)
Urs A. MeyerBiozentrum of the University of Basel
CH-4056 Basel, Switzerlandwww.biozentrum.unibas.ch/meyer.html
Falk Symposium No.156, Genetics in Liver DiseasesOctober 08-09, 2006 - Freiburg
PORPHYRIAS
Obscure diseases with confusing names
considered only when the need for a
diagnosis is desperate
(Antony McDonagh, 1997)
Porph1
PORPHYRINS (TETRAPYRROLES) ARE THE PIGMENTS OF LIFE
Chlorophyll
Vitamin B12
Heme
Parent molecule: Uroporphyrinogen IIIPorph6
PORPHYRINS
“The compounds which make grass green
and blood red” ( Hans Fischer, 1930 )
hamb/97
Porphyrins are intermediates in the
synthesis of heme (Fe-Protoporphyrin IXα)
HEMEPROTEINS
Hemoglobin
Myoglobin
Catalase
Mitochondrialcytochromes
Tryptophandioxygenase
Nitric oxide synthase
Guanylate cyclase
Microsomalcytochromes P450
PORPHYRIAS
Disorders resulting from partial
deficiencies in enzymes of heme
synthesis
hamb/97
PORPHYRIAS
Disorders resulting from partial
deficiencies in enzymes of heme
synthesis
hamb/97Meyer et al., N. Engl. J. Med. 286,1277-1282 ( 1972 )
Intermittent Acute Porphyria: demonstration of a genetic defect in porphobilinogen deaminase
Heme synthesis pathway
Glycine
Succinyl-CoA
HEME
Uro-porphyrinogen IIIProtoporhyrin
Hydroxymethylbilane
Aminolevulinic acid
Porphobilinogen
Copro-porphyrinogen III
Protoporphyrinogen
Fe2+
ALAD
Cpo
Uro-P Synthase
PBGD ( HMBS )
Uro-P decarboxylase
Proto-P oxidase
Ferrochelatase
ALAS
PROPOSED NOMENCLATURE FOR PORPHYRIAS
AcutePorphyrias
PBG-synthase deficiency
PBG-deaminase deficiency
(HMBS deficiency) (AIP)
Copro’gen oxidase deficiency (HCP)
Proto’gen oxidase deficiency (VP)
Uro’gen III synthase deficiency (CEP)
Uro‘gen decarboxylase deficiency (PCT)
Ferrochelatase deficiency (EPP)
CutaneousPorphyrias
Porph26
PORPHYRIASCLINICAL MANIFESTATIONS
SUNLIGHT-INDUCED SKIN LESIONS (PHOTOSENSITIVITY) DUE TO PORPHYRIN ACCUMULATION IN SKIN IN CUTANEOUS PORPHYRIAS
ATTACKS OF NEUROLOGIC DYSFUNCTIONASSOCIATED WITH ACCUMULATION OF THE PORPHYRIN PRECURSOR DELTA-AMINO-LEVULINIC ACID IN (INDUCIBLE) ACUTE PORPHYRIAS
Porph5
PORPHYRIASCLINICAL MANIFESTATIONS
SUNLIGHT-INDUCED SKIN LESIONS (PHOTOSENSITIVITY) DUE TO PORPHYRIN ACCUMULATION IN SKIN IN CUTANEOUS PORPHYRIAS
ATTACKS OF NEUROLOGIC DYSFUNCTIONASSOCIATED WITH ACCUMULATION OF THE PORPHYRIN PRECURSOR DELTA-AMINO-LEVULINIC ACID IN (INDUCIBLE) ACUTE PORPHYRIAS
Porph5
SYMPTOMS AND SIGNS OF INDUCIBLE ACUTE PORPHYRIAS
85 – 9543 – 8348 – 845 – 12
Abdominal painVomitingConstipationDiarrhea
Neuropsychiatric
CV, autonomic NS
Pain in extremities, back, chest, etc.ParesisRespiratory paralysisMental symptoms (agitation, confusion, hallucinations)Convulsions
TachycardiaArterial hypertension
Estimated incidence, %Gastrointestinal
50 – 7042 – 689 – 2040 – 5810 – 20
64 – 8536 - 55
Anderson et al., Ann. Int. Med. 142, 439-450, 2005
CHARACTERISTICS OF THE 4 INDUCIBLE ACUTE PORPHYRIAS
(combined prevalence ~5 cases / 100‘000 persons)
7~5ALA dehydratase(porphobilinogensynthase )
Autosomal recessive
ALA-dehydratasedeficientporphyria (ADP)
120~50Protoporphyrinogenoxidase
Autosomal dominants
Variegateporphyria (VP)
36~50Coproporphyrinogenoxidase
Autosomal dominant
Hereditarycoproporphyria(HCP)
227~50Porphobilinogen-deaminase ( HMBS)
Autosomal dominant
Acuteintermittentporphyria (AIP)
KnownMutations
Enzyme Activity
(% )
Deficient EnzymesInheritanceDisease(Abbreviation)
Anderson et al., Ann. Int. Med. 142, 439-450, 2005
PRECIPITATION OF ATTACKS IN ACUTE PORPHYRIAS
• DRUGS
• HORMONAL CAUSES
• INFECTION
• CALORIC RESTRICTION
• HEAVY SMOKING (?)
• ALCOHOL
• UNKNOWNPorph8
HEPATIC ACUTE PORPYHRIAS
QUESTIONS
- WHAT CAUSES NEUROLOGICAL DYSFUNCTION?
- HOW DO DRUGS, FASTING AND HORMONES
PRECIPITAE PORPHYRIA?
- WHAT ARE MECHANISMS OF APPARENTLY
BENEFICIAL EFFECTS OF CARBOHYDRATES
AND HEME?
Porph3
Attacks are always associated with ↑↑ hepatic ALAS1
HypothesisAll triggering factors directly upregulate ALAS1 at the
transcriptional level
2. How does fasting increase ALAS1?
1. How do drugs increase ALAS1?
3. What factors determine the liver specificALAS1 induction?
4. What else potentially activates ALAS1 and thereforetrigger attacks?
Nature Genetics12: 195-199, 1996
Vincent
Urinary excretion of ALA duringphenobarbital treatment
0 1 2 3 4 5 6 7 8 9 10
0.0
0.5
1.0
1.5
T1/T2 (male, n=2) T1/T2 (female, n=2) control (n=2)
ALA
(µm
ol/µ
mol
cre
atin
ine)
Day
INDUCTION OF ALAS IN PBGD-knockdown MICE
Drug-Response Elements of ALAS1
Human AGCTGGGTGAGCTAAGTTCATCTGTGCTGCCGTGACCTCTGMouse AGCTGGGTGAACCGAGTTCGTTTGCACTGCCTTGGCCTGTGRat AACTGGGTTAACTGAGTTCGTTTGTACTGCCTTGATCTGTG
* ****** * * ***** * ** ***** ** ** **
-16kb-21kb
Fraser, D. J.et al. (2002) J Biol Chem
Podvinec, M. .et al. (2004) PNAS
Fraser, D. J.et al. (2003) J Biol Chem
Mouse Rat
Human
Chicken
DR4 DR4
ALAS1
PXR CAR CXR
Xenosensors CAR and PXR mediateDrug Induction of ALAS1
Fraser et al. 2002, 2003; Podvinec et al. 2004
CAR/PXR ALAS1- 16kb
CYP3ACYP2B UGT1A1
Nuclear Hormone Receptor Family of Transcription Factors
Drug
Negative feedback regulation of ALAS1 by heme amplifiesthe response to drugs of ALAS1 in acute porphyrias
Urinary excretion of ALA duringphenobarbital treatment
0 1 2 3 4 5 6 7 8 9 10
0.0
0.5
1.0
1.5
T1/T2 (male, n=2) T1/T2 (female, n=2) control (n=2)
ALA
(µm
ol/µ
mol
cre
atin
ine)
Day
INDUCTION OF ALAS IN PBGD-knockdown MICE
What Triggers the FastingResponse ?
ALAS1 activity
0200400600800
10001200
fed fasted 16h
nm
ole
ALA
/g
liv
er/
h
ALAS1 mRNA
0
2
4
6
8
fed fasted 16hrel m
RN
A e
xp
ress
ion
** p < 0.01 fasted vs fed controll
Cell 122: 505-515, 2005
The mediator of the fastingresponse of ALAS1 is PGC-1α
PGC-1α
Versatile co-activator
GluconeogenesisLiver
Peroxisome Proliferator Activator Receptor γ Coactivator 1-α
TISSUE FUNCTION TFs
HNF4α, GR, FOXO1
NRF1FOXO1 HNF3βHNF3β ALAS1- 380 - 60
PGC-1α acts via FOXO1 and NRF1
Handschin et al. ( 2005 )
Fasting response is blunted in the absence of PGC-1α
ALAS1
Bile acids induce human ALAS1( Anne-Kathrin Peyer )
0
2
4
6
8
10
GFP VP16 FXR
Rel
mR
NA
Exp
ress
ion
vehicleGW4064
#
#
*
*
Human Liver Slice(MG Elferink, GM Groothuis,Diana Jung)
Cultures of Primary Human Hepatocytes
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
8h 16h 24h 8h 16h 24h 8h 16h 24h
Rel
mR
NA
Exp
ress
ion vehicle
10uM CDCA100uM CDCA
Donor A Donor B Donor C
0123456789
vehicle CDCA PB CDCA+PB
Rel
mR
NA
Exp
ress
ion
ALAS1ALAS1
ALAS1
Transcriptional Effects on ALAS1
PGC1α PGC1α PGC1αPGC1α PGC1α PGC1α PGC1α
-30kb -25kb -20kb -15kb -10kb -5kb 0 +20kb+15kb+10kb+5kb
HNF4αHNF4αHNF4α HNF4αHNF4α HNF4αHNF4α FXRCAR PXR
Xenobiotics EndobioticsBile Acids
ALAS1
NRF1
PGC1α
FOXO1
ALA, PBG ↑
Acute Neurovisceral Crisis
Fasting
PGC-1αCREB
Glucagon
cAMP
CONCLUSIONS
Induction of neurovisceral attacks in acute
porphyrias:
Drug-effects on ALAS1 are mediated by the
xenosensors CAR and PXR
Bile acids induce ALAS1 via activation of FXR
( clinical importance not known )
Fasting effects on ALAS1 are mediated via PGC-1α
HEPATIC ACUTE PORPYHRIAS
QUESTIONS
- WHAT CAUSES NEUROLOGICAL DYSFUNCTION?
- HOW DO DRUGS AND HORMONES PRECIPITATE
PORPHYRIA?
- WHAT ARE MECHANISMS OF APPARENTLY
BENEFICIAL EFFECTS OF CARBOHYDRATES
AND HEME?
Porph3
Raija Lindberg*Christoph Handschin*Adrian Roth*Carmela Gnerre*David Fraser*Michael Podvinec*
Sharon BlaettlerTaoufiq HarachDiana JungAnne-Kathrin PeyerFranck Rencurel
Maja MatisViola Tamasi
Renate LooserMichel R. KaufmannMarkus Beer
Urs A. Meyer GroupCore Program Genome Scale Biology
& BioinformaticsPharmacology/Neurobiology