COL4A4 – Autosomal Dominant Alport Syndrome

Autosomal dominant Alport syndrome (ADAS) is a type IV collagen nephropathy caused by heterozygous pathogenic variants in COL4A4, leading to defects in the α3α4α5(IV) network of the glomerular basement membrane. Patients typically present with microscopic hematuria, progressive proteinuria, and varying degrees of chronic kidney disease, with occasional sensorineural hearing loss and renal cysts enhancing phenotypic heterogeneity.

In a large Chinese kindred, a novel heterozygous missense variant, c.4195A>T (p.Met1399Leu), was identified in exon 44 of COL4A4 and segregated in all seven affected family members across two generations, while absent in 100 controls (7 probands) (PMID:28674241). In a separate three-generation pedigree, the known glycine substitution c.2510G>C (p.Gly837Ala) co-segregated with persistent hematuria and sensorineural hearing loss in 3 affected members, confirming an autosomal dominant pattern (3 probands) (PMID:31677115).

Case series further delineate the variant spectrum: three novel heterozygous COL4A4 mutations (p.Gly208Arg, p.Ser513GlufsTer2, p.Met1617CysfsTer39) were linked to ADAS, thin basement membrane nephropathy, or focal segmental glomerulosclerosis within single families, demonstrating genotype-phenotype overlap (3 variants) (PMID:29669314). A cohort of 31 patients with P/LP COL4A4 variants revealed a 52% prevalence of multicystic kidney disease associated with accelerated eGFR decline (mean cyst count 12.7 ±5.5; P=.006) and worse CKD outcomes (PMID:38178635).

Population-based screening of 157 individuals carrying COL4A3/COL4A4 P/LP variants showed a >2-fold higher prevalence of simple renal cysts versus general cohorts (50% vs. age-matched controls; P<.001), linked to age and eGFR but not proteinuria or gene locus (PMID:38317457). A case series of 17 families (42 individuals) with mono-allelic COL4A3/COL4A4 variants documented wide intrafamilial variability: all had hematuria, 33% progressed to kidney impairment, and 14% developed kidney failure by age 54 years (PMID:36925663).

Functional studies support a dominant-negative mechanism: heterozygous COL4A4 missense and frameshift variants yielded abnormal α4(IV) chains that incorporate into trimers but impair α345(IV) assembly, as shown by PCR-SSCP, direct sequencing, and split-luciferase trimerization assays, consistent with basement membrane thinning and splitting seen in patients (PMID:12028435).

References

• Journal of genetics • 2017 • Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family PMID:28674241
• CEN Case Reports • 2020 • Autosomal dominant Alport syndrome due to a COL4A4 mutation with an additional ESPN variant detected by whole-exome analysis PMID:31677115
• Cytogenetic and genome research • 2018 • Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes PMID:29669314
• Nephrology, dialysis, transplantation • 2024 • Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome PMID:38178635
• Nephrology, dialysis, transplantation • 2024 • Increased prevalence of kidney cysts in individuals carrying heterozygous COL4A3 or COL4A4 pathogenic variants PMID:38317457
• Kidney medicine • 2023 • Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families PMID:36925663
• Kidney international • 2002 • COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome PMID:12028435

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