title: VCP mutations are not a major cause of familial amyotrophic lateral sclerosis in the UK.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic.
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK.
authors.forename: Chun Tak
authors.initials: CT
authors.lastname: Kwok
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK.
authors.forename: Hsiang-Ya
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Morris
authors.affiliation: Centre for Neurodegeneration Research, Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, SE5 8AF, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.affiliation: Centre for Neurodegeneration Research, Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, SE5 8AF, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK. Electronic address: j.belleroche@imperial.ac.uk.
authors.forename: Jackie
authors.initials: J
authors.lastname: de Belleroche
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D042622:DNA Repeat Expansion; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D006113:United Kingdom; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis (ALS); Familial ALS (FALS); Frontotemporal dementia (FTD); Hexanucleotide repeat expansion; Inclusion body myopathy with Paget's disease of bone and fronto-temporal dementia (IBMPFD); Paget's disease of bone (PDB); Valosin containing protein (VCP)