A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features
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Transcript of A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features
A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features
Yoon H-S, Wilson JC & Eccles MRPathology, University of Otago,
Dunedin, New Zealand
Alport syndrome (AS)• A hereditary disorder resulting from abnormal
type IV collagen • Nephropathy with considerable genetic and
clinical heterogeneity characterized by haematuria, proteinuria and progressive renal failure, first reported by Alport in 1927
• Frequently associated with:– Eye abnormalities– High tone sensorineural deafness
• Rarely associated with:– Mental retardation– Leiomyomatois
Alport syndrome: genetics• 85% of AS patients: X-linked inheritance of
mutations in the COL4A5 gene on Xq22 encoding the 5(IV) collagen chain– COL4A5 is a large gene comprising 51 exons– As many as 609 mutations have been described to
date and are spread throughout the gene without any hot spots (Arup Laboratory 2011)
• 15%: Autosomal inheritance of mutations of the COL4A3 or COL4A4 gene encoding the 3(IV) or 4(IV) on 2q36-37:– 14%: autosomal recessive– 1%: autosomal dominant
Type IV collagen formation
Protomer(VI) chain
Meshwork formation
1
4
23
56
112
345
556
Hudson et al, NEJM 348:2543, 2003
NC1Collagenous7S
Type IV collagen distribution• 1.1.2(IV): Ubiquitously present in basement membrane
(BM) in many tissue• 3.4.5(IV) and 5.5.6(IV): Restricted tissue distribution– In the kidney 1.1.2(IV) network predominates during
early nephrogenesis in GBM.– During the 2nd trimester of foetal development,
3.4.5(IV) network gradually becomes dominant • 3.4.5(IV) is also expressed in the eye, cochlea, lung and
testis while 5.5.6(IV) network is present in skin, oesophagus and smooth muscle.
Initial presentation of the NZ family
• Two sisters (IV6:58 yo and IV8:54 yo) presented to the clinic to be considered as potential live kidney donors for their sons (V29:27 yo and V35:33 yo, respectively) who had ESRF.
• Both women were found to have significant proteinuria (1.8, 1.4g/d, respectively) and hypertension and they proceeded to a renal biopsy (mild mesangial proliferation and hypertensive arteriosclerosis).
• Routine questioning revealed a strong familial history of hypertension and the possibility of a familial form of renal disease.
• Subsequent clinical review of the family identified a number of additional family members with renal disease.
• Negative for hearing loss or eye abnormalities in all individuals tested.
Identif-ication number
Age (yrs old)Gender
Presentation Renal Function and Blood Pressure
Biopsy Inheritance
III2 F Died on dialysis Not done Affected/ Carrier
IV3 57M
ESRF. DialysisRenalTransplant at 41
Not done Affected
IV5 46M
ProteinuriaHypertension
Chronic kidney disease
Not done Affected
V24 39M
ProteinuriaHaematuria
Normal renal function
Mild mesangial matrix expansion
Affected
V29 27M
Acute nephritic syndromeHypertension
ESRF. Dialysis2nd renal transplant at 26
Chronic glomerulo-nephritis
Affected
V31 36M
ProteinuriaHypertension
Chronic kidney diseaseBP 136/86
Mesangial cell proliferation
Affected
V35 33M
ProteinuriaHaematuria
ESRF and renal transplant at 28
Chronic glomerulo-nephritis
Affected
IV39 72M
Proteinuria 1.6g/24 hrNo haematuriaHypertension
Mild chronic kidney diseaseBP 144/76
Not done Affected
V42 39M
Proteinuria 1.1g/24 hr
Normal renal functionBP 126/80
Mesangial cell proliferation
Affected
Identif-ication number
Age(yrs old)Gender
Presentation Renal Function and Blood Pressure
Biopsy Inheritance
IV26 58F
Proteinuria 1.8g/24 hr Hypertension
BP 152/76 Mesangial cell proliferationHypertensive arteriosclerosis
Carrier
IV28 54F
Proteinuria1.4g/24 hr Hypertension
Normal renal function
Mesangial cell proliferationHypertensive arteriosclerosis
Carrier
1. Subjects with renal disease identified before DNA tests
Dead:1, ESRF:3, Chronic disease:3
Histology of V42
IHC for 3, 4 and 5(IV)
3 4
5 Abs gift from Dr Sado
Diagnostic dilemma
• Is this Alport syndrome?– No hearing or eye abnormalities– Mild form of kidney disease and late onset• 11 Glomerulonephritis• 4 ESRF (3 males and 1 female) • Low penetrance!!
• A new entity of hereditary kidney disease?
Extended family pedigree
A total of 155 family members for 6 generations examined (81M and 74F).Black symbols: Biopsy confirmed GN (6M).Gray symbols: Clinically GN, biopsy not done (4M & 1F).Black dots: Obligate carriers (21F).White symbols: No clinical disease (71M & 73F).Cross: Confirmed by DNA testing.Predominance of GN in males and lack of male to male transmission consistent with X-linked inheritance
Family pedigree (simplified)
X-chromosomemicrosatellite marker
Two point LOD scores between the GN locus and markers mapping to chromosome Xq21.33-
23
Theta 0 0.01 0.05 0.1 0.2 0.3 0.4
DXS6809 -infinity -0.31 0.88 1.21 1.25 0.99 0.57
DXS6789 3.14 3.08 2.86 2.58 1.98 1.35 0.69
DXS8096 3.59 3.53 3.28 2.96 2.28 1.56 0.8
DXS1210 3.59 3.53 3.28 2.96 2.28 1.56 0.8
DXS6749 -infinity -0.61 -0.01 0.16 0.2 0.13 0.05
The linked region encompassing COL4A5
Nucleotide sequence alteration in COL4A5 in affected family members
Mae III digest of exon50 PCR products
M NC Affected males Affected & carrier females
A allelePresent in all affectedfamily members and not in 192 healthy control
Identif-ication number
Age (yrs old)Gender
Presentation Renal Function and Blood Pressure
Biopsy Inheritance
III2 F Died on dialysis Not done Affected/ Carrier
IV3 57M
ESRF. DialysisRenalTransplant at 41
Not done Affected
IV5 46M
ProteinuriaHypertension
Chronic kidney disease
Not done Affected
V24 39M
ProteinuriaHaematuria
Normal renal function
Mild mesangial matrix expansion
Affected
V29 27M
Acute nephritic syndromeHypertension
ESRF. Dialysis2nd renal transplant at 26
Chronic glomerulo-nephritis
Affected
V31 36M
ProteinuriaHypertension
Chronic kidney diseaseBP 136/86
Mesangial cell proliferation
Affected
V35 33M
ProteinuriaHaematuria
ESRF and renal transplant at 28
Chronic glomerulo-nephritis
Affected
IV39 72M
Proteinuria 1.6g/24 hrNo haematuriaHypertension
Mild chronic kidney diseaseBP 144/76
Not done Affected
V42 39M
Proteinuria 1.1g/24 hr
Normal renal functionBP 126/80
Mesangial cell proliferation
Affected
Identif-ication number
Age(yrs old)Gender
Presentation Renal Function and Blood Pressure
Biopsy Inheritance
IV24 69F
Trace microscopic haematuria
Normal renal functionBP 168/86
Not done Carrier
IV26 58F
Proteinuria 1.8g/24 hr Hypertension
BP 152/76 Mesangial cell proliferationHypertensive arteriosclerosis
Carrier
IV28 54F
Proteinuria1.4g/24 hr Hypertension
Normal renal function
Mesangial cell proliferationHypertensive arteriosclerosis
Carrier
IV31 69F
Hypertension Negative urine
Normal renal function
Not done Carrier
IV34 65F
Hypertension Negative urine
Normal renal function
Not done Carrier
IV36 61F
Microscopic haematuria
Normal renal function
Not done Carrier
V40 38F
Haematuria Normal renal functionBP 118/60
Mild mesangial cell proliferation
Carrier
IV47 54F
Negative urine BP 148/70 Not done Carrier
V44 36F
Intermittent microscopic haematuria
Normal renal functionBP 120/76
Not done Carrier
V49 43F
Negative urine Normal renal functionBP 120/70
Not done Carrier
V37 39F
Negative urine Normal renal function
Not done Carrier
1.Renal disease identified before DNA tests 2.Renal disease/carriers identified after DNA tests
Depiction of NC1 domain showing locations of cysteine sequence alterations and clinical details
of patients
Summary
We report a unique cysteine to tyrosine substitution in the NC1 domain of COL4A5 in a New Zealand family who presented with a phenotypically mild form of Alport syndrome, suggesting that in this family substitution of Cys1638Tyr led to late onset renal failure without hearing loss or eye abnormalities.
Histology of female carriers (IV26)
6A 6B
EM (carrier IV26)
150nm
EM (carriers IV26)
Summary
• Thin basement membrane nephropathy could be seen in some carrier women containing COL4A5 mutations.