Even patients with mild phenotype, namely isolated microhematuria (X-linked females with thin basement membrane on electron microscopy or heterozygous carriers of COL4A3 or COL4A4 mutations), can potentially progress to proteinuria and to end-stage renal disease.
Next generation sequencing of the patients who progressed to ESKDfailed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD.
In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD).
A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD).
We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure.
On the 129X1/SvJ background, Col4a3 -/- mice reached ESRF at approximately 66 days of age, while on the C57BL/6J background, the mean age at ESRF was 194 days of age.