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Abstract: Mutations in the optineurin (OPTN) gene have been associated with normal tension glaucoma and with amyotrophic lateral sclerosis (ALS). Here, we screened German familial ALS cases for OPTN mutations to gain additional insight into the spectrum and pathogenic relevance of this gene for ALS. One hundred familial German ALS cases and 148 control subjects were screened for OPTN mutations by sequence analysis of the complete OPTN coding sequence, and phenotypes of OPTN mutant patients were described. We identified a novel heterozygous truncating OPTN mutation p.Lys440Asnfs*8 in 1 ALS family with an aggressive ALS disease phenotype. This mutation abolishes protein domains crucial for nuclear factor κB signaling. Moreover, we detected 3 different nonsynonymous sequence variants, which have been described previously as risk factors for primary retinal ganglion cell degeneration in normal tension glaucoma. Two of them were detected on the same allele in a family that also carries a p.Asn352Ser disease mutation in the ALS gene TARDBP. All OPTN mutant patients presented with typical spinal onset ALS. Taken together, we detected a novel truncating OPTN mutation associated with an aggressive form of ALS and confirmed that OPTN mutations are a rare cause of ALS. In addition our data suggest that in some cases plausibly more than 1 mutation in OPTN or another ALS gene might be needed to cause ALS. Finally, our findings show that motoneurons and retinal ganglion cells, which are both projecting central nervous system neurons, might share common susceptibility factors. [Copyright &y& Elsevier]

Summary: Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. Methods: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. Findings: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0·012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3·28×10−6, odds ratio 1·58, 95% CI 1·30–1·91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0·00016). Interpretation: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis. [Copyright &y& Elsevier]

Abstract: Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca2+ permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS. [Copyright &y& Elsevier]

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 ( KIFAP3 ) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group. [ABSTRACT FROM AUTHOR]

Abstract: Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the “classic” ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival. [Copyright &y& Elsevier]