In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. It has been found to be associated with frontotemporal lobar degeneration (FTLD). In the present study, we have described homozygosity mapping and gene sequencing in a consanguineous autosomal recessive Pakistani family showing non-juvenile ALS without signs of FTLD. Gene mapping was carried out in all recruited family members using microsatellite markers, and linkage was established with sigma non-opioid intracellular receptor 1 (SIGMAR1) gene at chromosome 9p13.2. Gene sequencing of SIGMAR1 revealed a novel 3'-UTR nucleotide variation c.672*31A>G (rs4879809) segregating with disease in this family. The C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls. In silico analysis was carried out to explore the possible role of 3'-UTR variant of SIGMAR1 in ALS. The Regulatory RNA motif and Element Finder program revealed disturbance in miRNA (hsa-miR-1205) binding site due to this variation. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores due to this variation. Our results indicate that the 3'-UTR SIGMAR1 variant c.672*31A>G may have a role in the pathogenesis of ALS in this family.

Compound heterozygote mutations in the SIGMAR1 gene in an oldest‐old patient with amyotrophic lateral sclerosis

“…5 Homozygous SIGMAR1 mutations cause juvenile or young-onset ALS with no cognitive deficit. [6][7][8] Here, we identified a novel SIG-MAR1 mutation together with a common, but damaging, singlenucleotide polymorphism in an ALS patient with the oldest-old onset.…”

“…However, one of these families was subsequently identified as positive for the C9orf72 mutation, suggesting that the SIGMAR1 mutation does not exclusively explain the etiology at least in this family . Homozygous SIGMAR1 mutations cause juvenile or young‐onset ALS with no cognitive deficit . Here, we identified a novel SIGMAR1 mutation together with a common, but damaging, single‐nucleotide polymorphism in an ALS patient with the oldest‐old onset.…”

Structural basis for σ1 receptor ligand recognition

“…Instead, its nearest homolog is the yeast Δ8-Δ7 sterol isomerase, ERG2p, although the σ 1 receptor itself has no detectable isomerase activity 11 . Human genetic data have linked point mutants in σ 1 receptor to inherited motor neuron diseases [12][13][14] , and animal models implicate the receptor in Parkinson's disease 15 , addiction 16 , and pain 17 . A σ 1 receptor antagonist is currently in clinical trials for the treatment of neuropathic pain 7 , and agonists are in clinical trials for Alzheimer's disease 5 and ischemic stroke 6 .…”

The ALS-Related σ1R E102Q Mutant Eludes Ligand Control and Exhibits Anomalous Response to Calcium

“…σ1R is highly expressed in motor neurons [ 1 , 27 ], and autosomal recessive loss-of-function mutations in σ1R are primarily associated with distal hereditary motor neuropathy [ 10 , 46 , 47 ], and ALS/FTLD [ 23 , 48 ]. In vitro studies have revealed aberrant subcellular distribution of σ1R E102Q in NSC34 cells and have shown that cells expressing the mutant protein are more prone to apoptosis induced by ER stress than those expressing the WT protein [ 25 ].…”