title: 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.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid i Azam University, Islamabad, 44000, Pakistan.|PCR and Research Laboratories, Shifa College of Medicine, Shifa Tameer e Millat University, Islamabad, 44000, Pakistan.
authors.forename: Muhammad Ikram
authors.initials: MI
authors.lastname: Ullah
authors.affiliation: Division of Neurology, Shifa College of Medicine, Shifa International Hospital, Shifa Tameer e Millat University, Islamabad, 44000, Pakistan.
authors.forename: Arsalan
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid i Azam University, Islamabad, 44000, Pakistan.
authors.forename: Syed Irfan
authors.initials: SI
authors.lastname: Raza
authors.affiliation: Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, 54600, Pakistan.
authors.forename: Ali
authors.initials: A
authors.lastname: Amar
authors.affiliation: Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.affiliation: Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan.
authors.forename: Attya
authors.initials: A
authors.lastname: Bhatti
authors.affiliation: Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan.
authors.forename: Peter
authors.initials: P
authors.lastname: John
authors.affiliation: Section of Biochemistry, Shifa College of Medicine, Shifa Tameer e Millat University (STMU), Islamabad, 44000, Pakistan.
authors.forename: Aisha
authors.initials: A
authors.lastname: Mohyuddin
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid i Azam University, Islamabad, 44000, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan. mjh@asab.nust.edu.pk.
authors.forename: Muhammad Jawad
authors.initials: MJ
authors.lastname: Hassan
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003198:Computer Simulation; D003241:Consanguinity; D057180:Frontotemporal Dementia / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017480:Receptors, sigma / Q000235:genetics*; D000097605:Sigma-1 Receptor
chemical_list: D020413:3' Untranslated Regions; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: 3′-UTR; ALS; Pakistan; SIGMAR1