Abstract
Background: The COL2A1 gene encodes the α1 chain of type II collagen, a critical structural component in cartilage and the extracellular matrix. Mutations in this gene are associated with type II collagenopathies, including achondrogenesis type II (ACG2), a severe skeletal dysplasia characterized by perinatal lethality. This study aims to identify and characterize the molecular basis of a COL2A1 mutation in a patient presenting with ACG2 features and to elucidate the pathogenic mechanism of the mutation. Methods: A newborn with clinical signs of ACG2 underwent whole-exome sequencing (WES) for genetic analysis. Structural modeling was performed using AlphaFold2 to assess the mutation's impact on the collagen triple-helix. Functional studies were conducted using HEK-293 and C28/I2 cells transfected with wild-type or mutant COL2A1 to evaluate collagen synthesis and secretion via immunoblotting and ELISA. Results: WES identified a heterozygous missense mutation in COL2A1 gene (NM_001844.5: c.1584G>C, p.Glu532Gln). Structural modeling predicted that the mutation disrupted the stability of the triple-helix. Functional assays demonstrated increased synthesis and impaired secretion of type II collagen in cells expressing the mutant COL2A1 gene. Conclusions: The identified COL2A1 mutation (p.Glu532Gln) may lead to disrupted collagen structure and secretion, contributing to the pathogenesis of ACG2. These findings advance the understanding of COL2A1-related disorders and highlight the molecular mechanisms underlying type II collagenopathies.