Eymard-Pierre Eleonore, Yamanaka Koji, Haeussler Martin, Kress Wolfram, Gauthier-Barichard Fernande, Combes Patricia, Cleveland Don W, Boespflug-Tanguy Odile
Institut National de la Sante et de la Recherche Médicale U384 and Human Genetics Department, CHU, Clermont-Ferrand, France.
Ann Neurol. 2006 Jun;59(6):976-80. doi: 10.1002/ana.20879.
Recessive mutations in ALS2 (juvenile amyotrophic lateral sclerosis) are causative for early-onset upper motor neuron diseases, including infantile ascending hereditary spastic paralysis (IAHSP). The goal of this study is to identify novel disease-causing ALS2 mutations.
Mutations in ALS2 were screened by direct sequencing of complementary DNA obtained from patients' lymphoblasts.
We report a novel ALS2 missense mutation in patients affected by IAHSP. This homozygous G669A mutation in exon 4 is predicted to result in a tyrosine substitution at cysteine 156 of the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, leading to a loss of ALS2 function due to instability of mutant protein.
These results highlight the important role of the RCC1-like domain in ALS2 stability and function that is essential for upper motor neuron maintenance.
ALS2（青少年肌萎缩侧索硬化症）中的隐性突变是早发性上运动神经元疾病的病因，包括婴儿进行性遗传性痉挛性麻痹（IAHSP）。本研究的目的是鉴定新的致病ALS2突变。
通过对从患者淋巴母细胞获得的互补DNA进行直接测序来筛选ALS2中的突变。
我们报告了受IAHSP影响的患者中一种新的ALS2错义突变。外显子4中的这种纯合G669A突变预计会导致RCC1（染色质凝聚调节因子）样结构域的半胱氨酸156处的酪氨酸替代，该结构域编码一种假定的Ran鸟苷三磷酸酶鸟嘌呤交换因子，由于突变蛋白的不稳定性导致ALS2功能丧失。
这些结果突出了RCC1样结构域在ALS2稳定性和功能中的重要作用，而ALS2的稳定性和功能对于上运动神经元的维持至关重要。
