COL4A4 – Autosomal Recessive Alport Syndrome

COL4A4 encodes the α4 chain of type IV collagen, a critical component of the glomerular basement membrane (GBM). Homozygous or compound‐heterozygous variants in COL4A4 cause autosomal recessive Alport syndrome (Alport syndrome), characterized by hematuria, progressive proteinuria, sensorineural hearing loss and eventual renal failure. Carrier parents in recessive kindreds generally remain asymptomatic or exhibit isolated hematuria, supporting a dosage‐dependent mechanism of disease.

Assessing Clinical Validity

A total of 40 individuals from 20 families with two COL4A4 pathogenic variants have been reported, including 12 homozygotes and 28 compound heterozygotes, demonstrating consistent segregation with autosomal recessive Alport syndrome (PMID:24052634). In consanguineous and nonconsanguineous kindreds, all affected sibships showed biallelic COL4A4 changes, whereas unaffected relatives carried at most one variant (PMID:10074584). Immunohistochemical studies in an inbred family revealed complete absence of the α4 chain in GBM and preservation of α1, α2 and α6 chains, confirming the pathogenic mechanism in humans (PMID:10074584). These data meet ClinGen criteria for a Strong gene‐disease association.

Genetic Evidence

Inheritance is autosomal recessive, with carrier parents typically heterozygous and asymptomatic. Segregation analysis has identified two affected siblings in initial ARAS kindreds, with parents confirmed as heterozygotes (affected_relatives: 2). Case series include 40 probands harboring biallelic COL4A4 variants (PMID:24052634). The variant spectrum comprises >100 distinct lesions: missense Gly→X substitutions, frameshifts (e.g., c.1935_1952del (p.Pro647_Val652del)), nonsense mutations, splice‐site alterations, and in‐frame deletions (PMID:12748344). No recurrent founder variants have been conclusively established outside isolated populations. Population carrier frequencies support rarity and high penetrance in the homozygous state.

Functional / Experimental Evidence

Immunohistochemical analyses show absence of α4(IV) chain in GBM of ARAS patients, with normal α1/2/6 distribution, consistent with loss of heterotrimer assembly (PMID:10074584). In vitro assays in patient‐derived cells and split‐luciferase heterotrimerization tests have demonstrated defective α3α4α5(IV) assembly when COL4A4 variants are present, recapitulating GBM defects. Rescue experiments with wild‐type cDNA restore trimer formation, underscoring haploinsufficiency as the pathogenic mechanism.

Conflicting Evidence

No credible conflicting reports have been published disputing the COL4A4–Alport syndrome association. Phenotypic variability in heterozygous carriers (isolated hematuria vs. mild proteinuria) suggests influence of modifier genes or environmental factors but does not weaken the causal link.

Integration & Conclusion

Biallelic pathogenic variants in COL4A4 result in defective type IV collagen α3α4α5 trimer formation, leading to GBM thinning, splitting and progressive nephritis. Genetic evidence from >40 ARAS patients with consistent segregation and experimental data demonstrating chain absence in GBM converge on a clear haploinsufficiency mechanism. Further functional assays may refine genotype–phenotype correlations and inform prognosis.

Key Take-home: COL4A4 biallelic variants cause autosomal recessive Alport syndrome with high clinical validity, warranting inclusion in diagnostic panels and enabling accurate genetic counseling and early intervention.

References

• American journal of kidney diseases • 1998 • Molecular genetic and immunohistochemical study of autosomal recessive Alport's syndrome PMID:10074584
• Nephrology, dialysis, transplantation • 2003 • Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome PMID:12748344
• Journal of the American Society of Nephrology : JASN • 2013 • COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome PMID:24052634

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