COL4A3 – Autosomal recessive Alport syndrome

Autosomal recessive Alport syndrome (ARAS) is a progressive hereditary nephropathy characterized by early-onset microscopic hematuria, proteinuria, sensorineural hearing loss, and eventual renal failure. Biallelic pathogenic variants in COL4A3 (HGNC:2204), encoding the α3 chain of type IV collagen, disrupt α3α4α5(IV) heterotrimer formation in the glomerular basement membrane, leading to basement membrane thinning, thickening, and splitting. ARAS due to COL4A3 variants (MONDO:0008762) follows autosomal recessive inheritance, with heterozygous carriers often exhibiting mild hematuria without progression to end-stage kidney disease.

Genetic evidence for COL4A3 in ARAS is compelling. A systematic review identified 148 ARAS patients with biallelic COL4A3/COL4A4 variants from 26 studies (PMID:30717457), and a cohort of 30 genetically confirmed ARAS patients across 24 pedigrees demonstrated complete mutation detection with segregation in all families (PMID:24633401). Segregation analysis confirmed compound heterozygous or homozygous variants in affected individuals, with parents as obligate heterozygous carriers in each pedigree.

The variant spectrum encompasses glycine substitutions in the collagenous domain, truncating frameshifts, splice‐site changes, and large deletions. Recurrent LoF alleles include c.1927G>T (p.Gly640Arg) and c.2125G>T (p.Gly709Ter), whereas missense mutations such as c.1891G>A (p.Gly631Arg) are associated with early renal failure, lenticonus, and hearing loss (PMID:31925849). Heterozygous urinary abnormality–causing variants modulate disease severity: patients with urinary-abnormality alleles on both chromosomes reach ESKD at median age 15 years, versus 45 years when only one or no such variant is present (PMID:35369551).

Functional assays support a loss‐of‐function mechanism. Overexpression of COL4A3 G1334E in human podocytes induces endoplasmic reticulum stress and activation of the unfolded protein response, recapitulated in a Col4a3-G1332E knock-in mouse that develops an Alport phenotype (PMID:24262798). Splice‐mediated Alu insertion (c.4929-388G>T) abolishes normal α3(IV) chain expression and segregates with disease in a family (PMID:7633417).

Some glycine substitutions (e.g., Gly>Ala in COL4A4) are silent in homozygous carriers and present at up to 11.5% in controls, illustrating that not all collagenous alterations are pathogenic (PMID:9792860). Such exceptions underscore the importance of integrating functional data and segregation before assigning pathogenicity.

Collectively, extensive case series, segregation across ≥24 pedigrees, and concordant functional studies establish a Definitive gene–disease association for COL4A3 and ARAS. Molecular testing enables accurate diagnosis, prognostic stratification, and family counseling.

Key Take-home: Biallelic COL4A3 pathogenic variants cause ARAS via loss of α3(IV) chain function, and early genetic diagnosis guides clinical management and donor selection.

References

• Journal of clinical medicine • 2019 • Features of Autosomal Recessive Alport Syndrome: A Systematic Review PMID:30717457
• Pediatric nephrology (Berlin, Germany) • 2014 • Natural history of genetically proven autosomal recessive Alport syndrome PMID:24633401
• Journal of the American Society of Nephrology : JASN • 2014 • Evidence for activation of the unfolded protein response in collagen IV nephropathies PMID:24262798
• American journal of human genetics • 1998 • Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome PMID:9792860
• Kidney360 • 2020 • Heterozygous Urinary Abnormality-Causing Variants of COL4A3 and COL4A4 Affect Severity of Autosomal Recessive Alport Syndrome PMID:35369551

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