Highlights d ALS-causing mutations found within the gene encoding the glycosyltransferase GLT8D1 d Five ALS-associated GLT8D1 mutations proximate to the substrate binding site d GLT8D1 mutations exhibit in vitro cytotoxicity and impair enzyme activity d GLT8D1 mutations induce motor deficits in zebrafish consistent with ALS

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

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NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with Amyotrophic Lateral Sclerosis. Previously, a genome-wide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3,955 ALS patients and 2,276 unaffected controls and combined our results with previous reports.Meta-analysis on a total of 6,245 ALS patients and 5,051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG-repeat length (odds ratio = 1.50, P = 3.8x10 -5 ). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS. Keywords Amyotrophic lateral sclerosis; NIPA1; Repeat expansion M A N U S C R I P TA C C E P T E D ACCEPTED MANUSCRIPT (98%) the 5'-end of NIPA1 (NCBI: NM_144599.4) encodes for a stretch of 12 or 13 alanine residues of which 7 or 8 are encoded by a (GCG) n trinucleotide repeat (TNR), although both shorter and longer GCG stretches have been reported in non-affected individuals . In this previous study, an analysis of an international cohort of 2,292 ALS patients and 2,777 controls showed that "long" repeats (>8) in NIPA1 were enriched in ALS cases compared to controls (5.5% vs. 3.6%; OR 1.71; P = 1.6 x 10 -4 ) (Blauw et al., 2012).Although interesting and potentially relevant, only a small fraction of initially positive results from candidate gene studies (such as that performed on NIPA1) replicated PCR, sequencing and genotypingDutch samples obtained from 753 ALS and 603 unaffected individuals were analyzed using PCR according to protocols described previously and results were analyzed in a blinded and automated fashion with a call rate of 96.6% (Blauw, et al., 2012). Samples that failed genotyping, were additionally analyzed with Sanger sequencing to assess possible bias. An additional cohort of 767 unaffected controls and 764 ALS samples were genotyped using Sanger sequencing and automatically genotyped with a call rate of 99.1%. Primers: 5'-GCCCCTCTTCCTGCTCCT-3' (forward) and 5'-CGATGCCCTTCTTCTGTAGC -3' (reverse).Subgroup effects were meta-analyzed using both fixed and random effects modelling using the 'metafor' 2.0 package. For the joint analysis on individual data, we used a generalized linear model (GLM) with fixed-effects covariates: sex, method of genotyping and country of origin. We additionally applied generalized linear mixed model (GLMM) on nonimputed data to account for possible random effects.Programme (FP7/2007(FP7/ -2013). This study was supported by ZonMW under the frame of E-Rare-2, the ERA Net for Re...