A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate.
A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate.
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DOI：
10.1590/1678-4685-gmb-2020-0334
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发表时间：
2021
影响因子：
2.1
通讯作者：
Tang YP
中科院分区：
文献类型：
--
作者：
Xian C;Zhu M;Nong T;Li Y;Xie X;Li X;Li J;Li J;Wu J;Shi W;Wei P;Xu H;Tang YP
遗传性多发性外生骨病（HME）是一种罕见的骨骼疾病，其特征是形成多个良性软骨覆盖肿瘤，通常发生在长骨干骺端。超过70%的HME病例是由编码硫酸肝素合成酶（HS）的两个基因ext1和ext2的单等位基因突变引起的。为了鉴定更多的HME相关突变，我们使用全外显子组测序（WES）对5个独立的HME近亲家族成员的基因组DNA进行了测序。在v家族的三个受影响成员中均检测到ext2中一个新的杂合剪接位点突变（c.1173+2T>A），进一步的研究表明，该突变导致剪接时跳过ext2 mRNA的第7外显子，并在Arg360密码子后产生一个移码，从而出现新的43个密码子，随后出现一个终止密码子。虽然得到的截断蛋白仍然定位于高尔基体，类似于全长的EXT2，但其HS合成活性降低了40%。本研究在ext2中发现了一个新的剪接位点突变，提示是HME的致病突变，这可能会扩大HME的遗传病因谱，对临床遗传咨询和产前诊断有帮助。
Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by the formation of multiple benign cartilage-capped tumors, usually in the metaphyseal region of the long bones. Over 70% of HME cases arise from monoallelic mutations in either of the two genes encoding the heparan sulfate (HS) synthesis enzymes, ext1 and ext2. To identify more HME-associated mutations, genomic DNA from members of five independent consanguineous families with HME was sequenced with whole exome sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in ext2 was detected in all three affected members of family V. Further study showed that the novel mutation caused exon 7 of ext2 mRNA to be skipped during splicing and caused a frameshift after the codon for Arg360, which results in the appearance of new 43 codons, followed by a termination codon. Although the resulting truncated protein was still localized to the Golgi, similar to the full-length EXT2, its HS synthesis activity decreased by 40%. In this study, a novel splice site mutation in ext2 was identified and suggested to be a pathogenic mutation of HME, which may expand the genetic etiology spectrum of HME and may be helpful for clinical genetic counseling and prenatal diagnosis.