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A mutation in sigma‐1 receptor causes juvenile amyotrophic lateral sclerosis
Author(s) -
AlSaif Amr,
AlMohanna Futwan,
Bohlega Saeed
Publication year - 2011
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.22534
Subject(s) - biology , amyotrophic lateral sclerosis , genetics , mutation , c9orf72 , gene , allele , medicine , trinucleotide repeat expansion , disease , pathology
Abstract Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the brain and spinal cord, leading to muscle weakness and eventually death from respiratory failure. ALS is familial in about 10% of cases, with SOD1 mutations accounting for 20% of familial cases. Here we describe a consanguineous family segregating juvenile ALS in an autosomal recessive pattern and describe the genetic variant responsible for the disorder. Methods: We performed homozygosity mapping and direct sequencing to detect the genetic variant and tested the effect of this variant on a motor neuron‐like cell line model (NSC34) expressing the wild‐type or mutant gene. Results: We identified a shared homozygosity region in affected individuals that spans ∼120kbp on chromosome 9p13.3 containing 9 RefSeq genes. Sequencing the SIGMAR1 gene revealed a mutation affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma‐1 receptor. The mutated protein showed an aberrant subcellular distribution in NSC34 cells. Furthermore, cells expressing the mutant protein were less resistant to apoptosis induced by endoplasmic reticulum stress. Interpretation: Sigma‐1 receptors are known to have neuroprotective properties, and recently Sigmar1 knockout mice have been described to have motor deficiency. Our findings emphasize the role of sigma‐1 receptors in motor neuron function and disease. ANN NEUROL 2011;

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