Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome

Abstract

Hematuria in families with TBMD commonly segregates with the COL4A3/COL4A4 locus and thus results from mutations in the same genes as autosomal recessive Alport syndrome. Sometimes TBMD may be confused with the carrier state for X-linked Alport syndrome. However, nearly half of the families in this study had hematuria that did not segregate with the loci for either autosomal recessive or X-linked Alport syndrome.

Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

“…It is estimated that TBMN occurs in at least 1% of otherwise normal children and adults (25,27,28). Twenty to 50% of families with biopsy-proven TBMN have hematuria that is thought to segregate with COL4A3/4 mutations (5,7,10,20,(25)(26)(27). Our study proves the conjectural association between TBMN and the COL4A3 gene on an inductive rather than a deductive level, as done in human clinical studies before, and strengthens the above-mentioned epidemiologic figures for the incidence of TBMN.…”

“…In 20 to 50% of families with a clinical diagnosis of TBMN, the condition co-segregates with heterozygous COL4A3/4 mutations (5,7,10,20,25,26). Therefore, it now is the general consensus that the COL4A3/4 genes are involved in both the pathogenesis of autosomal AS and TBMN.…”

Thin Basement Membrane Nephropathy

“…This connection was verified at the gene level during the early 1990s, when the type IV collagen genes COL4A3, COL4A4, and COL4A5 were discovered and shown to be mutated in X-linked and autosomal Alport syndromes (37)(38)(39)(40)(41), with subsequent demonstration of mutations in COL4A3 and COL4A4 in TBMN (10). At present, 40% of TBMN cases have been associated with the COL4A3 and COL4A4 genes (23,42), but it remains to be verified whether female carriers who are carriers for a mutation in the COL4A5 gene can develop true TBMN. In principle, DNA-based diagnosis of TBMN is possible, but such tests are not commercially available.…”

“…Approximately two thirds of patients with TBMN have at least one other relative with hematuria (23). The remaining one third of patients may have de novo mutations or the nonpenetrance in other members of the family (82).…”

“…Thus, patients with TBMN that is linked to chromosome 2 are heterozygous for mutations in either COL4A3 or COL4A4, and they represent a carrier status for autosomal recessive Alport syndrome ( Figure 3A), in a similar manner as female individuals with mutations in one COL4A5 allele are carriers for X-linked Alport syndrome in male individuals ( Figure 3B). Savige et al (23) showed that up to 36% of TBMN cases associate with the COL4A3/COL4A4 locus for autosomal recessive Alport syndrome. More recently, several studies that aimed to identify mutations in the COL4A3 and COL4A4 genes, as well as their common promoter region, revealed that heterozygous mutations in these two genes are found in many patients with TBMN (15,23,24,34,42,90 -92).…”