Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature
Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature
复制标题
DOI：
10.1016/j.cca.2015.03.019
复制
发表时间：
2015-06-15
影响因子：
5
通讯作者：
Zhang, Qinghua
中科院分区：
文献类型：
--
作者：
Wang, Jian;Wang, Zhigang;Zhang, Qinghua
短指畸形包括由于趾骨、掌骨或两者发育异常而导致的手指缩短。它可以作为孤立的畸形发生，也可以作为许多先天性综合征的一部分与其他异常一起发生。在疾病分类学和遗传性骨骼疾病分类中，它被列为影响肢体的骨发育不全组之一。然而，短指（趾）畸形通常表现出高度的表型变异。在这项研究中，我们成功地确定了一个新的杂合突变的甲状旁腺激素样激素（PTHLH）基因的外显子组测序在中国家系短指和身材矮小。PTHLH基因编码甲状旁腺相关蛋白（PTHrP），参与软骨内骨发育的调节，该基因的突变导致E型短指（趾）畸形。突变p.L15R发生在信号肽的疏水核心区域，表明这种变异可能改变了计算机预测的信号肽切割位点。进一步的体外功能分析表明，这种突变可以导致保留的N-末端信号肽片段后，新生的蛋白质被翻译。(C)2015 Elsevier B. V.版权所有。
Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated. (C) 2015 Elsevier B.V. All rights reserved.