Heinritz Wolfram, Hüffmeier Ulrike, Strenge Sibylle, Miterski Bianca, Zweier Christiane, Leinung Steffen, Bohring Axel, Mitulla Beate, Peters Usha, Froster Ursula G
Institute of Human Genetics, Medical Faculty at the University of Leipzig, Leipzig, Germany.
Ann Hum Genet. 2009 May;73(Pt 3):283-91. doi: 10.1111/j.1469-1809.2009.00508.x. Epub 2009 Mar 25.
Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.
EXT1或EXT2基因的突变会导致多发性骨软骨瘤（MO），这是一种常染色体显性遗传病。本文报告了23名德国MO患者的临床发现以及这两个基因的分子分析结果。通过变性高效液相色谱法（dHPLC）和自动测序进行突变筛查。在23名患者中的17名中鉴定出了新的致病突变；11个在EXT1基因中，6个在EXT2基因中。5名患者是EXT2基因复发性突变的携带者（p.Asp227Asn、p.Gln172X、p.Gln258X），1名患者未检测到突变。为了证明它们对转录的致病作用，通过mRNA研究对EXT1和EXT2中的两个复杂突变以及三个剪接位点突变进行了特征分析。获得的结果为不同的异常剪接效应——新的隐蔽剪接位点的使用和外显子跳跃——提供了证据。我们的研究扩展了EXT1和EXT2基因突变的突变谱并增进了对其致病作用的理解。
