title: X-linked Alport syndrome in Hellenic families: phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5.
abstract: The X-linked Alport syndrome (ATS) is caused by mutations in COL4A5 and exhibits a widely variable expression. Usually ATS is heralded with continuous microhematuria which rapidly progresses to proteinuria, hypertension and chronic or end-stage renal disease (ESRD) by adolescence, frequently accompanied by sensorineural deafness and ocular complications. Milder forms of ATS also exist. We studied 42 patients (19M, 23F) of nine Hellenic families suspected clinically of X-linked ATS who presented with marked phenotypic heterogeneity. We identified mutations in COL4A5 in six families. Two males with nonsense mutation E228X reached ESRD by ages 14 and 18. Frameshift mutation 2946delT followed the same course with early onset renal involvement and deafness. However, two males with the milder missense mutation G624D, reached ESRD after 39 years and one patient showed thin basement membrane nephropathy (TBMN). Another 5/8 affected males with missense mutation P628L also developed ESRD between 30 and 57 years, while three exhibit only mild chronic renal failure (CRF). The data support previous findings that certain mutations are associated with milder phenotypes and confirm that mutation G624D may be expressed as TBMN with familial hematuria. Similar conclusions apply for missense mutation P628L. Interestingly, mutations G624D and P628L are near the 12th natural interruption of COL4A5 triple helical domain, which may explain the milder phenotype.
authors.affiliation: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: P
authors.initials: P
authors.lastname: Demosthenous
authors.forename: K
authors.initials: K
authors.lastname: Voskarides
authors.forename: K
authors.initials: K
authors.lastname: Stylianou
authors.forename: M
authors.initials: M
authors.lastname: Hadjigavriel
authors.forename: M
authors.initials: M
authors.lastname: Arsali
authors.forename: C
authors.initials: C
authors.lastname: Patsias
authors.forename: E
authors.initials: E
authors.lastname: Georgaki
authors.forename: P
authors.initials: P
authors.lastname: Zirogiannis
authors.forename: C
authors.initials: C
authors.lastname: Stavrou
authors.forename: E
authors.initials: E
authors.lastname: Daphnis
authors.forename: A
authors.initials: A
authors.lastname: Pierides
authors.forename: C
authors.initials: C
authors.lastname: Deltas
mesh_terms: D000293:Adolescent; D000328:Adult; D018389:Codon, Nonsense; D024141:Collagen Type IV / Q000235:genetics*; D003535:Cyprus / Q000453:epidemiology; D005260:Female; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006115:Greece / Q000453:epidemiology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009394:Nephritis, Hereditary / Q000150:complications / Q000235:genetics*; D010641:Phenotype
chemical_list: C478159:COL4A5 protein, human; D018389:Codon, Nonsense; D024141:Collagen Type IV