Presentation on theme: "A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of."— Presentation transcript:
1 A mild form of Alport syndrome: Hereditary nephropathy in the absence of extra-renal features Yoon H-S, Wilson JC & Eccles MR Pathology, University of Otago, Dunedin, New Zealand
2 Alport syndrome (AS)A hereditary disorder resulting from abnormal type IV collagenNephropathy with considerable genetic and clinical heterogeneity characterized by haematuria, proteinuria and progressive renal failure, first reported by Alport in 1927Frequently associated with:Eye abnormalitiesHigh tone sensorineural deafnessRarely associated with:Mental retardationLeiomyomatois
3 Alport syndrome: genetics 85% of AS patients: X-linked inheritance of mutations in the COL4A5 gene on Xq22 encoding the a5(IV) collagen chainCOL4A5 is a large gene comprising 51 exonsAs 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 a3(IV) or a4(IV) on 2q36-37:14%: autosomal recessive1%: autosomal dominant
4 Type IV collagen formation 7SCollagenousNC1a1a1a1a2a2a3a3a4a5a4a5a5a5a6a6a(VI) chainProtomerMeshwork formationHudson et al, NEJM 348:2543, 2003
5 Type IV collagen distribution a1.a1.a2(IV): Ubiquitously present in basement membrane (BM) in many tissuea3.a4.a5(IV) and a5.a5.a6(IV): Restricted tissue distributionIn the kidney a1.a1.a2(IV) network predominates during early nephrogenesis in GBM.During the 2nd trimester of foetal development, a3.a4.a5(IV) network gradually becomes dominanta3.a4.a5(IV) is also expressed in the eye, cochlea, lung and testis while a5.a5.a6(IV) network is present in skin, oesophagus and smooth muscle.
6 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.
7 1. Subjects with renal disease identified before DNA tests Identif-ication numberAge (yrs old) GenderPresentationRenal Function and Blood PressureBiopsyInheritanceIII2FDied on dialysisNot doneAffected/ CarrierIV357 MESRF. DialysisRenalTransplant at 41AffectedIV546MProteinuriaHypertensionChronic kidney diseaseV2439HaematuriaNormal renal functionMild mesangial matrix expansionV2927Acute nephritic syndrome2nd renal transplant at 26Chronic glomerulo-nephritisV3136BP 136/86Mesangial cell proliferationV3533ESRF and renal transplant at 28IV3972Proteinuria 1.6g/24 hrNo haematuriaMild chronic kidney diseaseBP 144/76V42Proteinuria 1.1g/24 hrBP 126/80Identif-ication numberAge(yrs old) GenderPresentationRenal Function and Blood PressureBiopsyInheritanceIV2658FProteinuria 1.8g/24 hr HypertensionBP 152/76Mesangial cell proliferationHypertensive arteriosclerosisCarrierIV2854Proteinuria1.4g/24 hr HypertensionNormal renal functionMesangial cell proliferation Hypertensive arteriosclerosisDead:1, ESRF:3, Chronic disease:3
10 IHC for a3, a4 and a5(IV)a3a4a5Abs gift from Dr Sado
11 Diagnostic dilemma Is this Alport syndrome? No hearing or eye abnormalitiesMild form of kidney disease and late onset11 Glomerulonephritis4 ESRF (3 males and 1 female)Low penetrance!!A new entity of hereditary kidney disease?
12 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 transmissionconsistent with X-linked inheritance
13 Family pedigree (simplified) X-chromosomemicrosatellite marker
14 Two point LOD scores between the GN locus and markers mapping to chromosome Xq21.33-23 Theta0.010.050.10.20.30.4DXS6809-infinity-0.310.818.104.22.1680.57DXS67893.143.082.862.581.981.350.69DXS80963.593.533.282.962.281.560.8DXS1210DXS6749-0.61-0.010.160.13The linked region encompassing COL4A5
15 Nucleotide sequence alteration in COL4A5 in affected family members G>A substitution at nucleotide 4913 in Exon 50 (asterisk)Resulting in Cys1638TyrMae III digest of exon50 PCR productsA allelePresent in all affectedfamily members and not in 192 healthy controlM NC Affected males Affected & carrier females
16 1.Renal disease identified before DNA tests 2.Renal disease/carriers identified after DNA testsIdentif-ication numberAge (yrs old) GenderPresentationRenal Function and Blood PressureBiopsyInheritanceIII2FDied on dialysisNot doneAffected/ CarrierIV357 MESRF. DialysisRenalTransplant at 41AffectedIV546MProteinuriaHypertensionChronic kidney diseaseV2439HaematuriaNormal renal functionMild mesangial matrix expansionV2927Acute nephritic syndrome2nd renal transplant at 26Chronic glomerulo-nephritisV3136BP 136/86Mesangial cell proliferationV3533ESRF and renal transplant at 28IV3972Proteinuria 1.6g/24 hrNo haematuriaMild chronic kidney diseaseBP 144/76V42Proteinuria 1.1g/24 hrBP 126/80Identif-ication numberAge(yrs old) GenderPresentationRenal Function and Blood PressureBiopsyInheritanceIV2469FTrace microscopic haematuriaNormal renal functionBP 168/86Not doneCarrierIV2658Proteinuria 1.8g/24 hr HypertensionBP 152/76Mesangial cell proliferationHypertensive arteriosclerosisIV2854Proteinuria1.4g/24 hr HypertensionMesangial cell proliferation Hypertensive arteriosclerosisIV31Hypertension Negative urineIV3465IV3661Microscopic haematuriaV4038HaematuriaBP 118/60Mild mesangial cell proliferationIV47Negative urineBP 148/70V4436Intermittent microscopic haematuriaBP 120/76V4943BP 120/70V3739
17 Depiction of NC1 domain showing locations of cysteine sequence alterations and clinical details of patients
18 SummaryWe 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.
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