COL4A6 – Alport Syndrome

Contiguous deletions involving the 5′ ends of COL4A5 and COL4A6 on Xq22 have been identified in 6 probands from 5 unrelated families presenting with X-linked Alport syndrome and diffuse leiomyomatosis (AS-DL), co-segregating with disease (4 families with initial deletion reports [PMID:7833948]; one additional family [PMID:12784310]). No isolated COL4A6 mutations were detected in a cohort of 250 male patients with hematuria and suspected Alport syndrome, despite screening exons 2, 12–14 of COL4A6 (0/250) (PMID:8738805). These structural variants encompass exon 1 of COL4A6 and extend variably into intron 2 or exon 3 in AS-DL pedigrees (e.g., deletion spanning from intron 2 of COL4A5 to intron 1 of COL4A6) (PMID:26179878; PMID:23958657).

Functional studies demonstrate normal steady-state COL4A6 mRNA levels but absence of α6(IV) protein at the dermal-epidermal junction in XLAS fibroblasts, implicating post-transcriptional loss (PMID:9749944). Proximal promoter analyses revealed a bidirectional regulatory element controlling COL4A5/COL4A6 co-expression, yet direct mechanistic links between COL4A6 disruption and GBM pathology remain unestablished (PMID:11096082). Together, these data support a Limited level of evidence for COL4A6 involvement in Alport syndrome, primarily as part of contiguous gene deletions rather than independent pathogenic variants.

Key take-home: COL4A6 contributes to X-linked Alport syndrome when co-deleted with COL4A5 but lacks independent pathogenic variants in classic AS cohorts, underscoring the diagnostic importance of deletion analysis in patients with AS-DL.

References

• Human mutation • 1994 • Deletion spanning the 5' ends of both the COL4A5 and COL4A6 genes in a patient with Alport's syndrome and leiomyomatosis. PMID:7833948
• American journal of medical genetics. Part A • 2003 • Alport syndrome with diffuse leiomyomatosis. PMID:12784310
• Journal of the American Society of Nephrology : JASN • 1996 • Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6 : a study of 250 patients with hematuria and suspected of having Alport syndrome. PMID:8738805
• Matrix biology : journal of the International Society for Matrix Biology • 1998 • Expression of mRNA for type IV collagen alpha1, alpha5 and alpha6 chains by cultured dermal fibroblasts from patients with X-linked Alport syndrome. PMID:9749944
• The Journal of biological chemistry • 2001 • Regulation of the paired type IV collagen genes COL4A5 and COL4A6. Role of the proximal promoter region. PMID:11096082

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