Col4a4, encoding the α4 chain of type IV collagen, is crucial as type IV collagen is a major component of the glomerular basement membrane (GBM) [1,2,3,5,6,8,9]. It is involved in maintaining the structure and function of the GBM, which is essential for kidney filtration. Mutations in Col4a4 can disrupt the normal assembly of type IV collagen in the GBM, affecting its integrity and leading to various kidney-related diseases [1,2,3,5,6,8,9].

Mutations in Col4a4 are associated with autosomal recessive and autosomal dominant Alport syndrome [2,3,5,6,9]. In autosomal recessive Alport syndrome, two pathogenic mutations in Col4a4 can lead to progressive renal failure, hearing loss, and ocular abnormalities [2]. Heterozygous pathogenic Col4a4 variants (autosomal dominant Alport syndrome) are common, and while they are not typically associated with end-stage kidney failure, hearing loss, or ocular abnormalities, affected individuals still have a higher risk of impaired kidney function compared to the general population [3]. In sporadic IgA nephropathy patients with thinned GBM lesions, diagnostic variants of Col4a4 were identified, and patients with these variants had different disease features such as higher proportions of GBM thickness <250 nm and milder glomerular injury [1].

In conclusion, Col4a4 is essential for the proper structure and function of the GBM. Studies on Col4a4-related mutations in mouse models, although not detailed in the provided abstracts but inferred from the human-disease associations, would likely help understand its role in Alport syndrome and IgA nephropathy. Understanding Col4a4 function and its mutations contributes to diagnosing and potentially treating these kidney-related diseases [1,2,3,5,6,9].

References:

1. Yuan, Xiaohan, Su, Qing, Wang, Hui, Zhu, Li, Zhang, Hong. 2022. Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients. In Journal of the American Society of Nephrology : JASN, 34, 132-144. doi:10.1681/ASN.2021111447. https://pubmed.ncbi.nlm.nih.gov/36130833/

2. Storey, Helen, Savige, Judy, Sivakumar, Vanessa, Abbs, Stephen, Flinter, Frances A. 2013. COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. In Journal of the American Society of Nephrology : JASN, 24, 1945-54. doi:10.1681/ASN.2012100985. https://pubmed.ncbi.nlm.nih.gov/24052634/

3. Savige, Judy. 2022. Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities. In Kidney international reports, 7, 1933-1938. doi:10.1016/j.ekir.2022.06.001. https://pubmed.ncbi.nlm.nih.gov/36090501/

4. Savige, Judy, Lipska-Zietkiewicz, Beata S, Watson, Elizabeth, Storey, Helen, Flinter, Frances. 2021. Guidelines for Genetic Testing and Management of Alport Syndrome. In Clinical journal of the American Society of Nephrology : CJASN, 17, 143-154. doi:10.2215/CJN.04230321. https://pubmed.ncbi.nlm.nih.gov/34930753/

5. Savige, Judy, Renieri, Alessandra, Ars, Elisabet, Lipska-Zietkiewicz, Beata, Gibson, Joel T. 2022. Digenic Alport Syndrome. In Clinical journal of the American Society of Nephrology : CJASN, 17, 1697-1706. doi:10.2215/CJN.03120322. https://pubmed.ncbi.nlm.nih.gov/35675912/

6. Kashtan, Clifford E. 2020. Alport Syndrome: Achieving Early Diagnosis and Treatment. In American journal of kidney diseases : the official journal of the National Kidney Foundation, 77, 272-279. doi:10.1053/j.ajkd.2020.03.026. https://pubmed.ncbi.nlm.nih.gov/32712016/

7. Deng, Haiyue, Zhang, Yanqin, Ding, Jie, Wang, Fang. 2022. Presumed COL4A3/COL4A4 Missense/Synonymous Variants Induce Aberrant Splicing. In Frontiers in medicine, 9, 838983. doi:10.3389/fmed.2022.838983. https://pubmed.ncbi.nlm.nih.gov/35386907/

8. Naylor, Richard W, Morais, Mychel R P T, Lennon, Rachel. 2020. Complexities of the glomerular basement membrane. In Nature reviews. Nephrology, 17, 112-127. doi:10.1038/s41581-020-0329-y. https://pubmed.ncbi.nlm.nih.gov/32839582/

9. Gregorio, Vanessa De, Caparali, Emine Bilge, Shojaei, Azadeh, Ricardo, Samantha, Barua, Moumita. 2023. Alport Syndrome: Clinical Spectrum and Therapeutic Advances. In Kidney medicine, 5, 100631. doi:10.1016/j.xkme.2023.100631. https://pubmed.ncbi.nlm.nih.gov/37122389/