Abstract 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.

中文翻译：

---

ext2的新突变通过减少硫酸乙酰肝素的合成而导致遗传性多个外生糖

摘要遗传性多发性外生糖（HME）是一种罕见的骨骼疾病，其特征是通常在长骨的干phy端区域形成多发良性软骨覆盖的肿瘤。超过70％的HME病例来自两个编码硫酸乙酰肝素（HS）合成酶ext1和ext2的基因中的单等位基因突变。为了鉴定更多与HME相关的突变，使用全外显子组测序（WES）对来自五个独立的近亲HME家族成员的基因组DNA进行了测序。在V族的所有三个受影响成员中均检测到ext2中一个新的杂合子剪接位点突变（c.1173 + 2T> A）。进一步的研究表明，该新突变导致ext2 mRNA的外显子7在剪接过程中被跳过，并导致移码在Arg360的密码子之后，导致出现了新的43个密码子，然后是终止密码子。尽管所得的截短蛋白仍位于高尔基体，类似于全长EXT2，但其HS合成活性降低了40％。在这项研究中，在ext2中发现了一个新的剪接位点突变，并被认为是HME的致病突变，这可能会扩大HME的遗传病因谱，并可能有助于临床遗传咨询和产前诊断。