Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants

被引:2
作者
Zhou, Bingna [1 ]
Gao, Peng [2 ]
Hu, Jing [1 ]
Lin, Xiaoyun [1 ]
Sun, Lei [1 ]
Zhang, Qian [1 ]
Jiang, Yan [1 ]
Wang, Ou [1 ]
Xia, Weibo [1 ]
Xing, Xiaoping [1 ]
Li, Mei [1 ,3 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Endocrinol, Key Lab Endocrinol,Natl Hlth & Family Planning Com, Beijing 100730, Peoples R China
[2] Chinese Acad Med Sci, Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Orthoped, Beijing 100730, Peoples R China
[3] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Endocrinol, Key Lab Endocrinol,Natl Hlth & Family Planning Com, Shuaifuyuan 1, Beijing 100730, Peoples R China
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
osteogenesis imperfecta; novel CRTAP variants; pathogenic mechanism; PROLYL; 3-HYDROXYLATION; CRTAP; MUTATIONS; DEFICIENCY; PATIENT; COMPLEX; LETHAL;
D O I
10.1210/clinem/dgae025
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 bones of patients with OI. Methods: Two nonconsanguineous families with CRTAP mutations were included and their phenotypes and genotypes were evaluated. Bone specimens were obtained from 1 patient with OI 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 alpha 1 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 patients with OI. 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 at Pro986 in the alpha 1 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 alpha 1 chain of type I collagen and impairs bone formation, thus contributing to severe OI type VII.
引用
收藏
页码:1803 / 1813
页数:11
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