COL4A5 and Associated Diseases
Expression & Function of COL4A5 Gene
The collagen alpha-5(IV) chain (COL4A5), an important component of human type IV collagen, is encoded by the COL4A5 gene on Xq22.3. As known to all, type IV collagen serves as the primary constituent of the glomerular basement membrane, and mutations in the COL4A5 gene prevent normal triple-helix formation and secretion of type IV collagen, resulting in defects in the glomerular basement membrane. Slits are secreted glycoproteins that bind to and activate Roundabout (Robo) receptors and function in axon guidance during development. Using a zebrafish model, scientists (Xiao, 2011) showed that Col4a5 on the surface of the tectum basement membrane could bind to Slit1 and guide retinal ganglion cell axons expressing Robo2.
COL4A5 and Related Disorders
More than 160 different mutations have been identified in the COL4A5 gene. The spectrum of mutations was broad and provided insight into the clinical variability of Alport syndrome with respect to age at renal failure and accompanying features.
- X-Linked Alport Syndrome
As early as 1994, scientists (Antignac, 1994) tested the COL4A5 gene in 88 unrelated male patients with X-linked Alport syndrome for major gene rearrangements by Southern blot analysis using COL4A5 cDNA probes. They detected 14 different deletions, which were dispersed all over the gene with different sizes ranging from 1 kb to the complete absence of the gene (more than 250 kb) in 1 patient. In 4 patients with intragenic deletions, the absence of the α-3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical methods. This finding supported the hypothesis that abnormalities of the alpha-5(IV) chain could prevent normal incorporation of the α-3(IV) chain into the glomerular basement membrane.
Fig. 1 Premature termination codon readthrough therapy in Alport syndrome. (Omachi, 2022)
- Digenic Inheritance disease
In addition to COL4A4, COL4A3 mutations also cause Alport syndrome, an autosomal recessive digenic inheritance disease. Massively parallel sequencing analysis (Mencarelli, 2015) has identified several Alport syndrome patients, and found that seven patients had a combination of mutations in COL4A3 and COL4A4, whereas 4 patients had 1 or 2 mutations in COL4A4 associated with a mutation in COL4A5. For each of these 11 probands, between 1 and 12 family members were recruited, for an average of 4 members per family. Altogether, 23 unique mutations were found, including 7 in COL4A3, 12 in COL4A4, and 4 in COL4A5. The mutations involved all domains of the collagen molecules, although the majority of missense mutations (11 of 13) affected the triple-helical collagenous domain, and 11 missense mutations substituted a critical glycine residue in this domain. Among the 8 patients with mutations in COL4A4 and COL4A5 (4 probands and 4 family members), the phenotypes included hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals.
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References
- Xiao, T.; et al. Assembly of lamina-specific neuronal connections by Slit bound to type IV Collagen. Cell. 2011, 146(1): 164-176.
- Antignac, C.; et al. Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression. The Journal of clinical investigation. 1994, 93, (3): 1195-207.
- Omachi, K.; et al. NanoLuc reporters identify COL4A5 nonsense mutations susceptible to drug-induced stop codon readthrough. iScience. 2022, 25(3): 103891.
- Mencarelli, M.A.; et al. Evidence of digenic inheritance in Alport syndrome. Journal of medical genetics. 2015, 52(3): 163-74.
