Hunter Michael, Angelicheva Dora, Tournev Ivailo, Ingley Evan, Chan Dick C, Watts Gerald F, Kremensky Ivo, Kalaydjieva Luba
Laboratory for Molecular Genetics, Western Australian Institute for Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands 6009, Australia.
Biochem Biophys Res Commun. 2005 Jul 15;332(4):982-92. doi: 10.1016/j.bbrc.2005.05.050.
Hereditary Motor and Sensory Neuropathy Lom (HMSNL) is a severe autosomal recessive peripheral neuropathy, the most common form of demyelinating Charcot-Marie-Tooth (CMT) disease in the Roma (Gypsy) population. The mutated gene, N-myc downstream-regulated gene 1 (NDRG1), is widely expressed and has been implicated in a range of processes and pathways. To gain an insight into NDRG1 function we performed yeast two-hybrid screening and identified interacting proteins whose known functions suggest involvement in cellular trafficking. Further analyses, focusing on apolipoproteins A-I and A-II, confirmed their interaction with NDRG1 in mammalian cells and suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in HMSNL. At the same time, the chromosomal location of NDRG1 coincides with a reported HDL-C QTL in humans and in mice. A putative role of NDRG1 in the general mechanisms of HDL-mediated cholesterol transport was supported by biochemical studies of blood lipids, which revealed an association between the Gypsy founder mutation, R148X, and decreased HDL-C levels.
遗传性运动和感觉神经病洛姆型（HMSNL）是一种严重的常染色体隐性周围神经病，是罗姆（吉普赛）人群中最常见的脱髓鞘型夏科-马里-图斯病（CMT）。突变基因N- myc下游调控基因1（NDRG1）广泛表达，并参与一系列过程和途径。为深入了解NDRG1的功能，我们进行了酵母双杂交筛选，并鉴定出相互作用蛋白，其已知功能表明它们参与细胞转运。进一步聚焦载脂蛋白A-I和A-II的分析，证实了它们在哺乳动物细胞中与NDRG1的相互作用，并提示雪旺细胞脂质转运缺陷是HMSNL的主要发病机制。同时，NDRG1的染色体定位与人类和小鼠中报道的高密度脂蛋白胆固醇（HDL-C）数量性状位点（QTL）一致。血脂生化研究支持了NDRG1在HDL介导的胆固醇转运一般机制中的假定作用，该研究揭示了吉普赛人始祖突变R148X与HDL-C水平降低之间的关联。
