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

作者：Al Saif Amr^*; Al Mohanna Futwan; Bohlega Saeed

来源：Annals of Neurology, 2011, 70(6): 913-919.

DOI：10.1002/ana.22534

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 similar to 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; 70: 913-919

• 出版日期2011-12