An investigation of recent and novel genetic variants that are associated with the pathogenesis of amyotrophic lateral sclerosis and their implications on phenotypes of the disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by loss of motor neurons in the spinal cord, brain stem and cerebral cortex. ALS is characterized by both upper and lower motor neuron symptoms and death usually occurs 3-5 years after onset. Familial histories are found in 5-10% of ALS cases while the rest are sporadic. This study is focused on analysing known and novel candidate genes in ALS and the aims of study are to characterize causal genes and risk factors for Familial ALS (FALS) and Sporadic ALS (SALS) in the Imperial Cohorts, in which genetic causes have been assigned for 64% of FALS cases. Three strategies were pursued and genes involved in proteostasis pathways were emphasized in this study. Firstly, we sequenced known candidate genes in our FALS cases excluded for known mutations. VCP and SQSTM1 genes were sequenced. We did not identify any coding changes in VCP but report a 5’ hexanucleotide expansion exclusively found in ALS. Known and novel SQSTM1 mutations, P392L and E155K, were identified in FALS kindred presenting with a history of Paget’s disease of bone. Secondly, we carried out association studies for two candidate genes on Chromosome 17, P4HB and NPLOC4, and showed that they were risk factors for FALS and SALS respectively. The association of P4HB SNPs with FALS survival time indicates that it is a modifier gene. Thirdly, to explore novel genes in ALS, we investigated Variable number tandem repeats (VNTR) from top candidate genes selected based on association signals from previous Genome wide association (GWA) studies and protein functions. VNTRs in NIPA1 and HSPB8 gene were associated with FALS and SALS respectively. Finally, we characterized the size of the reported hexanucleotide GGGGCC expansion in the C9orf72 gene using Southern blot analysis in our FALS cohort and interim results are presented.Open Acces