Osteogenesis imperfecta (OI) is a primary bone fragility disorder with an estimated prevalence of 1 in 15,000 births. The majority of OI cases are inherited in an autosomal‐dominant manner, while 5% to 10% have recessive or X‐linked inheritance. Up to now, approximately 5% of OI cases remain without mutation demonstrated, supporting the involvement of other genes in the disease spectrum. By whole‐exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta. CCDC134 encodes a secreted protein widely expressed and implicated in the regulation of some mitogen‐activated protein kinases (MAPK) signaling pathway. Western blot and immunofluorescence analyses confirmed the absence of CCDC134 protein in patient cells compared with controls. Furthermore, we demonstrated that CCDC134 mutations are associated with increased Erk1/2 phosphorylation, decreased OPN mRNA and COL1A1 expression and reduced mineralization in patient osteoblasts compared with controls. These data support that CCDC134 is a new gene involved in severe progressive deforming recessive osteogenesis imperfecta (type III). © 2020 American Society for Bone and Mineral Research.

中文翻译：

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CCDC134 中的纯合功能缺失突变是导致严重形式的成骨不全症的原因。

成骨不全症 (OI) 是一种原发性骨脆性疾病，估计每 15,000 名新生儿中就有 1 人患病。大多数 OI 病例以常染色体显性遗传方式遗传，而 5% 至 10% 为隐性或 X 连锁遗传。到目前为止，大约 5% 的 OI 病例仍未证实突变，这支持了疾病谱中其他基因的参与。通过全外显子组测序，我们在来自两个不相关家庭的三名患者中发现了 CCDC134 基因的纯合变异体 (c.2T>C)，这些患者患有严重的骨脆性，对双膦酸盐治疗无反应、身材矮小和纤细的长骨伴有假关节，但无牙本质发育不全。CCDC134编码一种广泛表达的分泌蛋白，并与某些丝裂原活化蛋白激酶 (MAPK) 信号通路的调节有关。与对照相比，蛋白质印迹和免疫荧光分析证实患者细胞中不存在 CCDC134 蛋白。此外，我们证明与对照组相比， CCDC134突变与 Erk1/2 磷酸化增加、OPN mRNA 和 COL1A1 表达降低以及患者成骨细胞矿化减少有关。这些数据支持CCDC134是一个涉及严重进行性变形隐性成骨不全症（III 型）的新基因。© 2020 美国骨与矿物研究学会。