COL4A5 – X-linked Alport Syndrome

X-linked Alport syndrome (MONDO:0010520) is a progressive hereditary nephropathy characterized by hematuria, proteinuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities. It is caused by pathogenic variants in COL4A5 (HGNC:2207), which encodes the type IV collagen α5 chain—a critical component of the glomerular basement membrane (GBM) (Gene Symbol). Affected males typically exhibit end‐stage renal disease (ESRD) by early adulthood, while heterozygous females display variable phenotypes due to X-inactivation.

Inheritance is X-linked recessive, with multiple variant types documented. The original splice donor mutation c.3454+1G>A was shown to induce exon 38 skipping in COL4A5 mRNA, leading to a truncated α5(IV) chain and juvenile‐onset ESRD with deafness in a male proband (PMID:8441246). Subsequent systematic screening of all 51 exons in 201 Italian families identified 30 distinct mutations—including glycine substitutions in the Gly-X-Y motif, frameshifts, nonsense, and splice-site variants—demonstrating a broad variant spectrum (PMID:8651296). Large intragenic deletions were detected in 9 of 177 additional families, correlating with severe early‐onset phenotypes (PMID:8599366).

Segregation analyses across multigenerational pedigrees confirm co-segregation of COL4A5 variants with disease. In the Italian cohort, rearrangements in COL4A5 cosegregated with juvenile Alport nephropathy in 9 unrelated families, supporting a causal relationship (PMID:8599366). In rare cases of somatic mosaicism, affected male offspring inherited large COL4A5 deletions from asymptomatic mosaic mothers, emphasizing the need to consider parental mosaicism in “sporadic” cases.

Functional studies have established mechanism of pathogenicity. A splice‐region variant c.1780-6T>G causes exon 25 skipping and a frameshift in collagen α5(IV) in minigene assays (PMID:28013382). A CRISPR/Cas9 mouse model harboring c.980_983del ATGG recapitulated GBM lamellation and absence of α5(IV), linking genotype to ultrastructural defects (PMID:36968823). Immunostaining of plucked hair follicles for α5(IV) provides a noninvasive diagnostic assay correlating with underlying splice defects.

Some reported variants have conflicting evidence. The Gly953Val missense (c.2858G>T) was once classified as pathogenic but was identified in multiple healthy individuals lacking hematuria or proteinuria, arguing against a sole causative role (PMID:31576025). This underscores the importance of combining genetic, segregation, and functional data for variant interpretation.

Collectively, the genetic and experimental data meet definitive ClinGen criteria. Early identification of COL4A5 mutations enables accurate diagnosis, prognosis, family counseling, and targeted management—including renin-angiotensin system blockade and emerging molecular therapies. Key take-home: Comprehensive genetic and functional assessment of COL4A5 variants is essential for precise diagnosis and personalized care in X-linked Alport syndrome.

References

• Kidney International | 1993 | COL4A5 splice site mutation and alpha 5(IV) collagen mRNA in Alport syndrome PMID:8441246
• Science | 1990 | Identification of mutations in the COL4A5 collagen gene in Alport syndrome PMID:2349482
• American Journal of Medical Genetics | 1995 | Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome PMID:8599366
• American Journal of Human Genetics | 1996 | X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene PMID:8651296
• Pediatric Nephrology | 2017 | Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome PMID:28013382
• European Journal of Human Genetics | 2020 | Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families PMID:31576025
• Frontiers in Medicine | 2023 | A mouse model for X-linked Alport syndrome induced by Del-ATGG in the Col4a5 gene PMID:36968823

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