COL4A5 – Alport Syndrome

COL4A5 encodes the type IV collagen α5 chain, a critical component of the glomerular basement membrane (GBM). X-linked Alport syndrome (XLAS; MONDO:0018965) arises when pathogenic COL4A5 variants disrupt type IV collagen α3–α4–α5 heterotrimer formation, leading to GBM thinning, splitting, and lamellation. Clinically, male patients present with persistent microscopic hematuria (HP:0000790), progressive proteinuria (HP:0000093), sensorineural hearing loss (HP:0000365), and ocular anomalies; heterozygous females show variable penetrance.

Genetic evidence for COL4A5–Alport association is definitive. Systematic screening of 131 unrelated X-linked families identified 64 missense (predominantly glycine substitutions in Gly-X-Y repeats) and 35 truncating variants, including nonsense and frameshifts (131 families) (PMID:8940267). Segregation of variants with disease phenotype has been confirmed in at least 23 multi-generation kindreds with consistent X-linked inheritance (PMID:12105244).

The variant spectrum spans glycine substitutions (e.g., c.3614G>T (p.Gly1205Val)), splice-site alterations, small insertions/deletions, and large rearrangements. Recurrent hypomorphic alleles like c.1871G>A (p.Gly624Asp) are associated with milder phenotypes and later onset renal failure, underscoring genotype–phenotype variability.

Functional studies support pathogenicity. A Col4a5 R471X knock-in mouse exhibits absent α5(IV) expression, GBM irregular thickening/lamination, progressive proteinuria, hematuria, and end-stage renal disease mirroring human XLAS (PMID:30582011). In vitro splicing assays of canonical donor-site mutants confirm exon skipping and truncated transcripts, validating mRNA splicing defects.

Genotype–phenotype correlations show truncating mutations predict earlier ESRD (mean age ~20 years) than non-truncating variants (mean age ~30 years), guiding prognostic counseling and early intervention (PMID:12105244). Hypomorphic alleles may require individualized monitoring strategies.

In conclusion, COL4A5 variants cause definitive X-linked Alport syndrome. Comprehensive genetic testing, including sequencing and copy-number analysis, is essential for diagnosis, family screening, and guiding renin-angiotensin blockade to delay renal progression. COL4A5 should be included in diagnostic panels for hereditary nephritis.

References

• American Journal of Human Genetics • 1996 • Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. PMID:8940267
• Nephrology, dialysis, transplantation • 2002 • Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. PMID:12105244
• Biochemistry and biophysics reports • 2019 • Establishment of X-linked Alport syndrome model mice with a Col4a5 R471X mutation. PMID:30582011

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