Hunter Michael, Bernard Rafaëlle, Freitas Elizabeth, Boyer Amandine, Morar Bharti, Martins Ian J, Tournev Ivailo, Jordanova Albena, Guergelcheva Velina, Ishpekova Boryana, Kremensky Ivo, Nicholson Garth, Schlotter Beate, Lochmüller Hanns, Voit Thomas, Colomer Jaume, Thomas P K, Levy Nicolas, Kalaydjieva Luba
Laboratory of Molecular Genetics, Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, Australia.
Hum Mutat. 2003 Aug;22(2):129-35. doi: 10.1002/humu.10240.
In a previous study, we have shown that N-myc downstream-regulated gene 1 (NDRG1), classified in databases as a tumor suppressor and heavy metal-response protein, is mutated in hereditary motor and sensory neuropathy Lom (HMSNL), a severe autosomal recessive form of Charcot-Marie-Tooth (CMT) disease. The private founder mutation R148X, causing HMSNL in patients of Romani ethnicity, has so far remained the only molecular defect linking NDRG1 to a specific disease phenotype. Here we report the first study aiming to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded. Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. The phenotype of the IVS8-1G>A homozygote was very closely related to that of HMSNL patients. In addition, we have detected homozygosity for the known R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. No other variants were identified in the coding sequence, whereas 12 single nucleotide polymorphisms were observed in the introns. Hum Mutat 22:129-135, 2003.
在之前的一项研究中，我们已经表明，N- myc下游调控基因1（NDRG1），在数据库中被归类为肿瘤抑制因子和重金属反应蛋白，在遗传性运动和感觉神经病Lom（HMSNL）中发生突变，这是夏科-马里-图斯（CMT）病的一种严重常染色体隐性形式。导致罗姆族患者患HMSNL的私人奠基者突变R148X，迄今为止仍然是将NDRG1与特定疾病表型联系起来的唯一分子缺陷。在此我们报告了第一项旨在评估该基因在排除CMT病最常见病因的情况下对周围神经病发病机制总体贡献的研究。对104名不同种族的CMT患者的NDRG1进行序列分析，确定了一个新的致病突变，IVS8-1G>A（g.2290787G>A），该突变影响IVS8的剪接受体位点并导致外显子9的跳跃。IVS8-1G>A纯合子的表型与HMSNL患者的表型非常密切相关。此外，我们在两名受影响个体中检测到已知R148X突变的纯合性。因此，NDRG1突变在我们的整个患者组中占2.88%，在脱髓鞘性神经病患者中占4.68%。在编码序列中未发现其他变异，而在内含子中观察到12个单核苷酸多态性。《人类突变》2003年第22卷：129 - 135页 。
