Sfar Sana, Abid Abderrazak, Mahfoudh Wijden, Ouragini Houyem, Ouechtati Farah, Abdelhak Sonia, Chouchane Lotfi
Department of Molecular Immuno-Oncology, Faculty of Medicine, University of Monastir, Monastir, Tunisia.
Mol Biol Rep. 2009 Apr;36(4):661-7. doi: 10.1007/s11033-008-9226-3. Epub 2008 Mar 11.
Hereditary multiple exostoses (HME) is an autosomal dominant orthopaedic disorder most frequently caused by mutations in the EXT1 gene. The aim of the present study is to determine the underlying molecular defect of HME in two multigenerational Tunisian families with 21 affected members and to examine the degree of intrafamilial variability. Linkage analysis was performed using three microsatellite markers encompassing the EXT1 locus and mutation screening was carried out by direct sequencing. In family 1, evidence for linkage to EXT1 was obtained on the basis of a maximum LOD score of 4.26 at theta = 0.00 with D8S1694 marker. Sequencing of the EXT1 revealed a heterozygous G > T transversion (c.1019G>T) in exon 2, leading to a missense mutation at the codon 340 (p.Arg340Leu). In family 2 we identified a novel heterozygous 1 bp deletion in the exon 1 (c.529_531delA) leading to a premature codon stop and truncated EXT1 protein expression (p.Lys177LysfsX15). This mutation was associated with the evidence of an intrafamilial clinical variability and considered to be a novel disease-causing mutation in the EXT1 gene. These findings provide additional support for the involvement of EXT1 gene in the HME disease.
遗传性多发性骨软骨瘤（HME）是一种常染色体显性遗传性骨科疾病，最常见的病因是EXT1基因突变。本研究的目的是确定两个拥有21名患病成员的突尼斯多代家族中HME的潜在分子缺陷，并研究家族内的变异程度。使用涵盖EXT1基因座的三个微卫星标记进行连锁分析，并通过直接测序进行突变筛查。在家族1中，基于D8S1694标记在θ = 0.00时最大LOD得分为4.26，获得了与EXT1连锁的证据。EXT1基因测序显示外显子2中存在杂合的G > T颠换（c.1019G>T），导致密码子340处的错义突变（p.Arg340Leu）。在家族2中，我们在外显子1中鉴定出一个新的杂合1 bp缺失（c.529_531delA），导致密码子提前终止和EXT1蛋白表达截短（p.Lys177LysfsX15）。该突变与家族内临床变异性的证据相关，被认为是EXT1基因中的一种新的致病突变。这些发现为EXT1基因参与HME疾病提供了额外的支持。
