title: A genetic association study of two genes linked to neurodegeneration in a Sardinian multiple sclerosis population: the TARDBP Ala382Thr mutation and C9orf72 expansion.
abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the χ(2) test with a standard 2×2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS.
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy. Electronic address: lorena.lorefice@hotmail.it.
authors.forename: L
authors.initials: L
authors.lastname: Lorefice
authors.affiliation: Multiple Sclerosis Center, ASL8-Department of Medical Sciences, University of Cagliari, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Murru
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fenu
authors.affiliation: Multiple Sclerosis Center, ASL8-Department of Medical Sciences, University of Cagliari, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Corongiu
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Frau
authors.affiliation: Multiple Sclerosis Center, ASL8-Department of Medical Sciences, University of Cagliari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cuccu
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: G C
authors.initials: GC
authors.lastname: Coghe
authors.affiliation: Institute of Neurology, ASL8-Department of Medical Sciences, University of Cagliari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Tranquilli
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Multiple Sclerosis Center, Department of Medical Sciences, University of Cagliari, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Marrosu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D011159:Population Surveillance / Q000379:methods; D011506:Proteins / Q000235:genetics*; D013912:Threonine / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C000598624:TARDBP protein, human; D013912:Threonine; D000409:Alanine
keywords: C9orf72 expansion; Genetic background; MS pathogenesis; Neurodegeneration; Sardinian population; TARDBP Ala382Thr mutation