Alport retinopathy results from "severe" COL4A5 mutations and predicts early renal failure.
OBJECTIVE
Previous studies of X-linked Alport syndrome demonstrated that "severe" COL4A5 mutations (large deletions and rearrangements, nonsense and frame-shift mutations, and glycine substitutions in the carboxy-terminal residues) were associated with early-onset renal failure, hearing loss, and lenticonus in affected male patients. This study examined whether severe mutations also resulted in the typical perimacular dot-and-fleck retinopathy.


METHODS
Twenty unrelated families with X-linked Alport syndrome were studied for the causative mutation in the COL4A5 gene. Nineteen affected male and 22 affected female individuals aged at least 14 yr from these families were examined for clinical and, in particular, ophthalmologic features.


RESULTS
Nineteen pathogenic mutations were identified in the COL4A5 gene in the 20 families using a thermal melt analyzer (HRM RotorGene 6000; Corbett) or direct sequencing of hair root or skin fibroblast cDNA. Fifteen mutations were classified severe and four as moderate. Severe mutations were associated with the central dot-and-fleck Alport retinopathy in male individuals (P = 0.0256) in addition to early-onset renal failure, hearing loss, and lenticonus (P = 0.0009, 0.009, and 0.009, respectively). Severe mutations did not correlate with clinical features in female individuals.


CONCLUSIONS
Severe mutations in male individuals with X-linked Alport syndrome are associated with the perimacular dot-and-fleck retinopathy. Furthermore, the retinopathy indicates that male individuals are at increased risk for renal failure before the age of 30 (P = 0.0007).
Tan
Rachel
R
University of Melbourne, Northern Health, Northern Hospital, Epping VIC 3076, Australia.
Colville
Deb
D
Wang
Yan Yan
YY
Rigby
Lin
L
Savige
Judy
J
D000293:Adolescent; D000328:Adult; D024141:Collagen Type IV / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009394:Nephritis, Hereditary / Q000150:complications* / Q000235:genetics*; D011379:Prognosis; D051437:Renal Insufficiency / Q000209:etiology*; D012164:Retinal Diseases / Q000209:etiology*; D012720:Severity of Illness Index; D055815:Young Adult
C478159:COL4A5 protein, human; D024141:Collagen Type IV