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.

Genotype‐phenotype study in patients with valosin‐containing protein mutations associated with multisystem proteinopathy

“…Our cohort of patients recruited in North America included individuals of mixed European descent, Brazilian families, an African‐American family and a family of Hispanic/Apache descent . Among families of European ancestry, patients of German, Italian, Spanish, Austrian, Belgian, French, Irish, and British backgrounds have been identified. In Asia, Korean, Japanese, and Chinese, families have been reported.…”

A Mighty “Protein Extractor” of the Cell: Structure and Function of the p97/CDC48 ATPase

“…Mutations in at least 18 genes have been identified in familial ALS. Among them, p97 mutations account for less than 2% (Johnson et al, 2010; Koppers et al, 2012; Kwok et al, 2015). There are 18 reported mutations appearing in 12 different positions.…”

Mutations in the Human AAA+ Chaperone p97 and Related Diseases

“…In these cases, more than one individual in the family develops ALS and sometimes family members have FTD as well. Mutations in at least 18 genes have been identified in FALS cases, with mutations in the p97 gene contributing <1–2% (Table 1) (Johnson et al, 2010; Koppers et al, 2012; Kwok et al, 2015). …”