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Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis
Author(s) -
EymardPierre Eleonore,
Yamanaka Koji,
Haeussler Martin,
Kress Wolfram,
GauthierBarichard Fernande,
Combes Patricia,
Cleveland Don W.,
BoespflugTanguy Odile
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20879
Subject(s) - missense mutation , mutation , genetics , biology , mutant protein , amyotrophic lateral sclerosis , upper motor neuron , mutant , hereditary spastic paraplegia , gene , phenotype , medicine , disease , pathology
Objective 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. Methods Mutations in ALS2 were screened by direct sequencing of complementary DNA obtained from patients' lymphoblasts. Results 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. Interpretation These results highlight the important role of the RCC1‐like domain in ALS2 stability and function that is essential for upper motor neuron maintenance. Ann Neurol 2006;59:976–980