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Ann Neurol. 2011 Dec;70(6):913-9. doi: 10.1002/ana.22534. Epub 2011 Aug 12.

A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. amr@kfshrc.edu.sa

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 ~120 kbp 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.

PMID:
21842496
DOI:
10.1002/ana.22534
[Indexed for MEDLINE]

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