Genetic analysis, phenotype spectrum and functional study of rare osteogenesis imperfecta caused by CRTAP Variants

Bingna Zhou; Peng Gao; Jing Hu; Xiaoyun Lin; Lei Sun; Qian Zhang; Yan Jiang; Ou Wang; Weibo Xia; Xiaoping Xing; Mei Li

doi:10.1210/clinem/dgae025

Genetic analysis, phenotype spectrum and functional study of rare osteogenesis imperfecta caused by CRTAP Variants

J Clin Endocrinol Metab. 2024 Jan 12:dgae025. doi: 10.1210/clinem/dgae025. Online ahead of print.

Authors

Bingna Zhou¹, Peng Gao², Jing Hu¹, Xiaoyun Lin¹, Lei Sun¹, Qian Zhang¹, Yan Jiang¹, Ou Wang¹, Weibo Xia¹, Xiaoping Xing¹, Mei Li¹

Affiliations

¹ Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
² Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China.

PMID: 38214665
DOI: 10.1210/clinem/dgae025

Abstract

Objective: Deficiency of cartilage-associated protein (CRTAP) can cause extremely rare autosomal recessive osteogenesis imperfecta (OI) type VII. We investigated the pathogenic mechanisms of CRTAP variants through functional studies on OI patient-derived bones.

Methods: Two nonconsanguineous families with CRTAP mutations were included, and their phenotypes and genotypes were evaluated. Bone specimens were obtained from one OI patient and a normal control during orthopedic surgery. The impacts of the novel variant on the CRTAP transcript were confirmed. The expression levels of CRTAP mRNA and CRTAP protein were analyzed. The quantification of prolyl 3-hydroxylation in the α1 chain of type I collagen was evaluated.

Results: Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities. The c.621 + 1G > A and c.1153-3C > G mutations were identified in CRTAP in the OI patients. The c.621 + 1G > A variant was a novel mutation that could impair mRNA transcription, leading to a truncated CRTAP protein. In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased, and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was simultaneously accompanied by significantly reduced prolyl 3-hydroxylation of Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone.

Conclusion: The novel c.621 + 1G > A mutation in CRTAP expands the genotypic spectrum of type VII OI. Biallelic mutations of c.621 + 1G > A and c.1153-3C > G in CRTAP can lead to reduced CRTAP mRNA and deficient CRTAP protein in osteoblasts, which reduces 3-hydroxylation in Pro986 of the α1 chain of type I collagen and impairs bone formation, thus contributing to severe OI type VII.

Keywords: novel CRTAP variants; osteogenesis imperfecta; pathogenic mechanism.