Col4a3, encoding the alpha-3 chain of type IV collagen, is crucial for the formation of the collagen IV α3α4α5 heterotrimers in basement membranes [2]. These heterotrimers play a vital role in maintaining the structural integrity of basement membranes in various tissues, especially in the glomeruli of the kidneys, cochlear, and ocular basement membranes [3]. Mutations in Col4a3 are associated with Alport syndrome, a disorder characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities [1,3]. Genetic models, such as transgenic mice with Col4a3 mutations, are valuable for studying its function and the pathogenesis of related diseases [2].

In a transgenic Alport syndrome mouse model with a Col4a3 p.G799R mutation, the mutation led to a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum, causing defective secretion and persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway was involved in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, an endoplasmic reticulum stress inhibitor, effectively improved kidney function in vivo [2].

In conclusion, Col4a3 is essential for the proper formation and function of basement membranes, especially in the kidneys. The study of Col4a3-mutated mouse models has provided insights into the pathogenesis of Alport syndrome, particularly in relation to endoplasmic reticulum stress and the MyD88/p38 MAPK pathway. This understanding may help develop new treatment strategies for Alport syndrome and other related kidney diseases [2].

References:

1. 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/

2. Yu, Shuwen, Gu, Xiangchen, Zheng, Qimin, Jin, Yuanmeng, Xie, Jingyuan. 2024. Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation. In Kidney international, 106, 433-449. doi:10.1016/j.kint.2024.04.015. https://pubmed.ncbi.nlm.nih.gov/38782199/

3. 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/