Col4a3, encoding the alpha-3 chain of type IV collagen, is crucial for the formation of the collagen IV α3α4α5 heterotrimers in the basement membranes, such as those in the glomeruli, cochlear, and ocular tissues [1,2,3]. Mutations in Col4a3 can disrupt the normal structure and function of these basement membranes, leading to various renal and extrarenal manifestations.

Mutations in Col4a3 are associated with autosomal recessive Alport syndrome, which is characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities [1]. In a study of 40 individuals with autosomal recessive inheritance, 50% of the mutation pairs affected Col4a3 [1]. Also, a transgenic mouse model with a Col4a3 mutation (p.G799R) showed pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers, abnormal accumulation of mutant collagen IV α3 chains in the endoplasmic reticulum, and defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro [2]. RNA-seq analysis revealed the involvement of the MyD88/p38 MAPK pathway in mediating subsequent inflammation and apoptosis signaling activation [2].

In conclusion, Col4a3 is essential for the proper structure and function of basement membranes. The study of Col4a3-mutated mouse models has helped clarify the pathogenesis of Alport syndrome-related kidney injuries, especially in glomeruli, highlighting the role of Col4a3 in maintaining normal kidney function and the significance of understanding its function in the context of this genetic kidney disease [1,2].