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目的:研究一个腓骨肌萎缩症2型(Chareot-Marie-Tooth Disease type2,CMT2)大家系的临床及遗传学特征,定位和克隆该家系的致病基因用于分子诊断。方法:采集山东省一个CMT2大家系,采用家系分析法观察该家系的遗传规律,并采用连锁分析试剂盒(Version 2.5)进行全基因组扫描,用LINKAGE软件(Version 5.1)中的MLINK程序作连锁分析,运用直接测序法对20个候选基因的外显子及外显子-内含子边界区序列进行测序,结果用CHROMOSOME软件进行序列分析。结果:该CMT2家系符合常染色体显性遗传的特征,连锁分析表明位于10p14存在一个致病基因位点,测序分析显示脱氢酶E1和转酮酶结构域1(DHTKD1)的一个无义突变[c.1455T>G(p.Tyr485*)]存在于该家系的所有8个患者中,而不存在于该家系任何未受累者及250名正常对照者中。结论:本研究结果提示DHTKD1的无义突变可能是CMT2发病的分子基础。
OBJECTIVE: To study the clinical and genetic features of a pedigree of the Chareot-Marie-Tooth Disease type 2 (CMT2) family and to locate and clone the pedigree’s causative genes for molecular diagnosis. Methods: A pedigree of CMT2 in Shandong Province was collected. The pedigree was used to analyze the genetic rule of this pedigree. Genome-wide scanning was carried out by using the Version 2.5 analysis kit. Linkage analysis was carried out by MLINK program in LINKAGE software (Version 5.1) , Sequenced the exon and exon-intron border region sequences of 20 candidate genes using direct sequencing and the results were analyzed by CHROMOSOME software. Results: The CMT2 pedigree was consistent with the characteristics of autosomal dominant inheritance. Linkage analysis showed that there was a virulence locus located at 10p14. Sequencing analysis showed a nonsense mutation of dehydrogenase E1 and transketolase domain 1 (DHTKD1) c.1455T> G (p.Tyr485 *)] was present in all eight patients in the pedigree but not in any non-affected pedigree and 250 normal controls. Conclusion: The results of this study suggest that the nonsense mutation of DHTKD1 may be the molecular basis of the pathogenesis of CMT2.