Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX
Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX
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DOI：
10.1002/jbmr.4277
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发表时间：
2021-03-19
影响因子：
6.2
通讯作者：
Oheim, Ralf
中科院分区：
文献类型：
--
作者：
Stuerznickel, Julian;Jaehn-Rickert, Katharina;Oheim, Ralf
已知多个基因与成骨不全症（OI）相关，成骨不全症是一种表型和遗传异质性骨骼疾病，主要特征是骨矿物质密度低和骨折风险增加。最近，影响MESD的突变被描述为引起纯合子儿童常染色体隐性OI XX，MESD编码内质网中低密度脂蛋白受体LRP 5和LRP 6运输所需的伴侣蛋白。在本研究中，对一个家庭中的三个死胎进行全外显子组测序，以评估遗传性疾病的存在。为了进一步表征骨骼表型，进行了胎儿尸检、骨组织学和定量背散射电子成像（qBEI），并将结果与年龄匹配的正常骨骼表型对照组进行比较。在每个受影响的个体中，检测到MESD外显子2和外显子3的复合杂合突变。根据骨骼表型，其特征是多个子宫内骨折和严重的骨骼畸形，OI XX被诊断为这些人。MESD标本的组织学评价显示骨发育受损，骨细胞形态改变，小管连接减少。此外，通过qBEI分析骨密度分布表明，MESD突变个体的基质矿化比对照组受损且更异质。与先前报道的OI XX个体表型相反，本研究中更严重的表型可能由位于MESD分子伴侣结构域内的外显子2突变解释，该突变导致功能完全丧失，这表明MESD与早期骨骼发育相关。(c)2021年，任作家。《骨与矿物质研究杂志》由Wiley Periodicals LLC代表美国骨与矿物质研究学会（ASBMR）出版。
Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared with those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..