The nuclear factor κB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset
The nuclear factor κB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset
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DOI：
10.1086/518900
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发表时间：
2007-07-01
影响因子：
9.8
通讯作者：
Verellen-Dumoulin, Christine
中科院分区：
文献类型：
--
作者：
Maystadt, Isabelle;Rezsohazy, Rene;Verellen-Dumoulin, Christine
下运动神经元疾病 (LMND) 包括多种临床和遗传异质性疾病。通过研究一个大型近交非洲家族，我们最近描述了一种新型常染色体隐性 LMND 变异，其特征为儿童期发病、全身肌肉受累和严重后果，并将该疾病基因定位到染色体 1p36 上的 3.9-cM 间隔。我们鉴定了包含 Pleckstrin 同源结构域的 G 家族成员 5 基因 PLEKHG5 的纯合错义突变（约 1940 T -> C [p. 647 Phe -> Ser]）。在瞬时转染的 HEK293 和 MCF10A 细胞系中，我们发现野生型 PLEKHG5 激活核因子 kappa B (NF kappa B) 信号通路，并且突变型 PLEKHG5 蛋白的稳定性和细胞内位置都发生改变，严重损害 NFkB 转导通路。此外，在瞬时转染的 NSC34 小鼠运动神经元中观察到聚集体，该神经元过度表达突变型 PLEKHG5 蛋白。 PLEKHG5 功能的丧失和聚集体的形成可能会导致这种新型 LMND 的神经毒性。
Lower motor neuron diseases (LMNDs) include a large spectrum of clinically and genetically heterogeneous disorders. Studying a large inbred African family, we recently described a novel autosomal recessive LMND variant characterized by childhood onset, generalized muscle involvement, and severe outcome, and we mapped the disease gene to a 3.9-cM interval on chromosome 1p36. We identified a homozygous missense mutation (c. 1940 T -> C [p. 647 Phe -> Ser]) of the Pleckstrin homology domain-containing, family G member 5 gene, PLEKHG5. In transiently transfected HEK293 and MCF10A cell lines, we found that wild-type PLEKHG5 activated the nuclear factor kappa B (NF kappa B) signaling pathway and that both the stability and the intracellular location of mutant PLEKHG5 protein were altered, severely impairing the NFkB transduction pathway. Moreover, aggregates were observed in transiently transfected NSC34 murine motor neurons overexpressing the mutant PLEKHG5 protein. Both loss of PLEKHG5 function and aggregate formation may contribute to neurotoxicity in this novel form of LMND.