VCP mutations are not a major cause of familial amyotrophic lateral sclerosis in the UK

Chun Tak Kwok, Hsiang Ya Wang, Alex G. Morris, Bradley Smith, Christopher Shaw, Jackie De Belleroche*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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.-221220insCTGCCACTGCCACTGCCG, 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.

Original languageEnglish
Pages (from-to)209-213
Number of pages5
JournalJournal of the Neurological Sciences
Issue number1-2
Early online date16 Jan 2015
Publication statusPublished - 15 Feb 2015


  • 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)


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