ABSTRACT Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and frequent fractures. The disorder is caused by pathogenic variants in genes that encode type I collagen. The COL1A1 gene encodes the pro‐α1 (I) collagen chain, which assembles with another pro‐α1 (I) chain and one pro‐α2 (I) chain to form a heterotrimeric triple helix. The C‐terminal propeptide (C‐propeptide) contributes to molecular recognition and initiation of triple helix formation, thereby promoting correct chain alignment during procollagen biosynthesis. Variants in this region may disrupt chain association and folding, and impair collagen assembly. Here, we present the case of a Japanese male infant who presented with respiratory distress, pulmonary hypoplasia, recurrent fractures, and hearing loss. Radiographic examination revealed slender long bones with multiple acute and healing fractures in the ribs, clavicles, and limbs, as well as Wormian bones. Genetic analysis identified a de novo heterozygous COL1A1 variant, NM₀00088. 4: c. 4223A>G, p. (Tyr1408Cys). Based on the clinical and molecular findings, the patient was diagnosed with OI type III. The patient received bisphosphonate therapy and respiratory support with continuous positive airway pressure. In silico structural modeling suggested that Tyr1408 is located near the C‐propeptide interface, where it may contribute to local stability through aromatic and hydrogen‐bonding interactions. Substitution by cysteine could alter the local folding environment and inter‐chain interactions. Presently, the report provides clinical and structure‐based context for how cysteine substitutions in the C‐terminal region of COL1A1 may be associated with severe OI phenotypes.
Watanabe et al. (Thu,) studied this question.