Background: Thin basement membrane nephropathy (TBMN) is often caused by mutations in the COL4A3 and COL4A4 genes.
Methods: We examined 62 unrelated individuals diagnosed with TBMN by renal biopsy (N= 49, 79%) or a positive family history of hematuria but without a biopsy (N= 13, 21%) for mutations in the COL4A3 gene and the COL4A3/COL4A4 promoter. All 52 exons of COL4A3 as well as the COL4A3/COL4A4 promoter were screened with single-stranded conformational polymorphism (SSCP) analysis at 4 degrees C and at room temperature. Amplicons that demonstrated electrophoretic abnormalities were sequenced.
Results: Seven mutations were demonstrated in seven patients: G532C and G584C in exon 25, G596R in exon 26, G695R in exon 28, and IVS 2224 - 11C>T, IVS 2980 + 1G>A and IVS 3518 - 7C>G. No mutations were found in the COL4A3/COL4A4 promoter. Four novel polymorphisms or variants (P116T in exon 6, P690P in exon 27, and G895G and A899A in exon 33) were also demonstrated. In addition, P1109S and Q1495R, which had been described previously but whose status was unclear, were shown to be polymorphisms. All seven mutations described here were associated with hematuria. While one mutation (2980 + 1G>A) was found in an individual who also had proteinuria, none of her family members with the same mutation had increased urinary protein. None of the patients with these seven mutations had renal impairment. Hematuria was completely penetrant in families with the G532C, G584C, G596R, and IVS 2980 + 1G>A mutations but not with the G695R and IVS 3518 - 7C>G mutations.
Conclusion: COL4A3 mutations are common in TBMN.