title: Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron diseases (MND), while frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia. Many ALS families segregating FTLD have been reported, particularly over the last decade. Recently, mutations in TARDBP, FUS/TLS, and C9ORF72 have been identified in both ALS and FTLD patients, while mutations in VCP, a FTLD associated gene, have been found in ALS families. Distinct variants located in the 3'-untranslated region (UTR) of the SIGMAR1 gene were previously reported in three unrelated FTLD or FTLD-MND families. We directly sequenced the coding and UTR regions of the SIGMAR1 gene in a targeted cohort of 25 individual familial ALS cases of Caucasian origin with a history of cognitive impairments. This screening identified one variant in the 3'-UTR of the SIGMAR1 gene in one ALS patient, but the same variant was also observed in 1 out of 380 control chromosomes. Subsequently, we screened the same samples for a C9ORF72 repeat expansion: 52% of this cohort was found expanded, including the sample with the SIGMAR1 3'-UTR variant. Consequently, coding and noncoding variants located in the 3'-UTR region of the SIGMAR1 gene are not the cause of FTLD-MND in our cohort, and more than half of this targeted cohort is genetically explained by C9ORF72 repeat expansions.
authors: Centre of Excellence in Neurosciences of Université de Montréal, CHUM Research Center, Montreal, Québec, Canada.
authors: Véronique V
authors: VV
authors: Belzil
authors: Hussein
authors: H
authors: Daoud
authors: William
authors: W
authors: Camu
authors: Michael J
authors: MJ
authors: Strong
authors: Patrick A
authors: PA
authors: Dion
authors: Guy A
authors: GA
authors: Rouleau
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003704:Dementia / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics; D017480:Receptors, sigma / Q000235:genetics*; D000097605:Sigma-1 Receptor
chemical_list: D020413:3' Untranslated Regions; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins; D011506:Proteins; D034702:RNA-Binding Protein FUS; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C568651:C9orf72 protein, human