COL4A3 – Alport Syndrome

Alport syndrome is a hereditary nephritis characterized by progressive hematuria, proteinuria, sensorineural hearing loss, and ocular anomalies. The α3 chain of type IV collagen, encoded by COL4A3 (HGNC:2204), is a critical component of the glomerular basement membrane. Pathogenic variants in COL4A3 cause autosomal recessive and, less commonly, autosomal dominant forms of Alport syndrome (MONDO:0018965), with onset of end-stage kidney disease in early adulthood for recessive cases and variable penetrance for dominant cases.

Extensive genetic evidence supports a definitive association of COL4A3 with Alport syndrome. Over 100 unrelated probands have been reported with biallelic COL4A3 variants in autosomal recessive families demonstrating classic basement membrane splitting on electron microscopy and co-segregation with disease, often in consanguineous pedigrees ([PMID:11134255]). Segregation studies across multiple families have identified at least 19 additional affected relatives carrying pathogenic COL4A3 alleles ([PMID:9269635]). Heterozygous carriers manifest thin basement membrane nephropathy or late-onset proteinuria, consistent with gene-dosage effects.

The variant spectrum includes glycine substitutions in the Gly-X-Y collagenous motif, loss-of-function frameshifts, splice-site mutations, and in-frame deletions. A recurrent hotspot, c.2083G>A (p.Gly695Arg), has been described in both recessive and dominant contexts ([PMID:24130771]). Founder alleles such as c.40_63del (p.Leu14_Leu21del) in Ashkenazi Jews ([PMID:23927549]) and c.1315G>A (p.Gly439Ser) in Turkish families ([PMID:23297803]) illustrate population-specific enrichment.

Functional studies establish a loss-of-function mechanism: aberrant splicing with intronic Alu insertions, exon skipping, and ER retention activate the unfolded protein response in podocytes ([PMID:24262798]). CRISPR/Cas9 knock-in of COL4A3 truncating alleles in podocyte models recapitulates ER stress and apoptosis, while minigene assays confirm splicing defects for c.765G>A (p.Thr255=) ([PMID:39424670]). Animal models expressing Gly1334Glu develop glomerular basement membrane thinning and proteinuria, with partial rescue upon RAAS blockade ([PMID:25514610]; [PMID:27904025]).

No compelling evidence disputes the COL4A3–Alport syndrome link. Variants classified as benign by in silico tools often lack segregation and functional concordance, underscoring the necessity of integrating molecular and clinical data ([PMID:33851121]).

In summary, COL4A3 meets ClinGen criteria for a definitive gene–disease relationship with Alport syndrome. Genetic testing for COL4A3 variants informs prognosis, guides early renoprotective therapy, and enables accurate family counseling. Key Take-home: COL4A3 pathogenic variants are definitive causes of autosomal Alport syndrome and should prompt early genetic screening in familial hematuria and proteinuria.

References

• Nephrol. Dial. Transplant. • 1997 • Autosomal dominant Alport syndrome linked to the type IV collagen α3 and α4 genes PMID:9269635
• J. Am. Soc. Nephrol. • 2001 • Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome PMID:11134255
• PLoS One • 2013 • Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria PMID:24130771
• Clin. Genet. • 2014 • A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population PMID:23927549
• Genet. Test. Mol. Biomarkers • 2013 • A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family PMID:23297803
• JASN • 2014 • Evidence for activation of the unfolded protein response in collagen IV nephropathies PMID:24262798
• Kidney Int. • 2002 • COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome PMID:12028435
• Nephrol. Dial. Transplant. • 2016 • Early RAAS blockade exerts renoprotective effects in autosomal recessive Alport syndrome PMID:27904025

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