Mild Forms of Alport Syndrome: Hereditary Nephropathy in the Absence of Extra-Renal Features

Abstract

Objective: Mutations in the type IV collagen gene, COL4A5, are associated with Alport syndrome (AS), characterized by glomerulonephropathy and end-stage renal failure (ESRF), characteristic ophthalmic signs and hightone sensorineural deafness. Approximately 600 mutations of COL4A5 have been identified, including alterations in the non-collagenous NC1 domain. Method: We performed linkage analysis and sequencing to identify the mutation in a New Zealand family with Alport syndrome and late-onset renal failure without hearing loss or eye abnormalities. Results: We report a novel Cys1638Tyr alteration in the NC1 domain of COL4A5, identified in a moderately large family, eight of whom were confirmed by renal biopsy to have nephropathy. Only three of eight mutant males progressed to ESRF. The remaining five mutant males exhibit either chronic renal disease at ages 36, 46 and 72 or as yet show no renal disease at ages 39 and 39. Extra-renal manifestations were absent from all family members carrying the mutation. Conclusion: This subsitutional mutation is the first reported to affect the tenth of 12 cysteine residues in the NC1 domain and is compared with other mutations involving the NC1 domain reported previously. We also review mild forms of AS and discuss the relationship between AS and benign familial nephropathy.