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Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genomewide significant result (P ‫؍‬ 1.84 ؋ 10 ؊8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5, 6) account for Ϸ5% of cases. Rare familial cases arise from mutations in genes encoding the vesicle-associated membrane associated protein B (7), alsin (a RAB5-guanine nucleotide exchange factor) (8, 9), senataxin (10) or dynactin (11). Recently, we reported that Ϸ5% of familial ALS cases are due to mutations in the FUS/TLS gene (12, 13) whose product binds DNA and RNA, as does TARDBP. The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14-25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies. Examples include the identification of IL2RA and IL7RA variants as risk factors for multiple sclerosis (26-28) and the recent reports of 6 new gene regions associated with type 2 diabetes (29)(30)(31)(32)(33)(34)(35). To test the hypothesis that commonly occurring genetic

Three clustered, homologous paraoxonase genes (PON1, PON2 and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS we have identified at least seven PON gene mutations that are predicted to alter PON function.

Background The misfolding and prion‐like propagation of the protein α‐synuclein (α‐syn) is the leading molecular signature in Parkinson's disease (PD). There is a significant coincidence of PD and melanoma that may suggest a shared pathophysiology. This study compared the presence of α‐syn in neural crest‐derived tissues, such as nevi, melanoma, skin tags, and skin biopsies from patients with PD and healthy controls. Methods Biopsies from participants with PD were obtained from patients from a tertiary referral center for dermatology and neurology in Mexico and a private dermatopathology center in Florida between January 2015 and March 2016. Biopsies from 7 patients with melanoma, 15 with nevi, 9 with skin tags, 8 with PD, and 9 skin biopsies from healthy volunteers were analyzed for immunohistochemical determination of α‐syn and tyrosinase. All analyses were performed by pathologists who were blinded with respect to the clinical diagnosis. Results In healthy controls, positive α‐syn status was restricted to scattered cells in the basal layer of the epidermis and accounted for 1 ± 0.8% of the analyzed area. In patients with PD, there was increased staining for α‐syn PD (3.3 ± 2.3%), with a higher percentage of positive cells in nevi (7.7 ± 5.5%) and melanoma (13.6 ± 3.5%). There was no increased staining in skin tags compared with healthy controls. Conclusion Patients with PD and melanoma have increased staining for α‐syn in their skin. The authors propose that neurons and melanocytes, both derived from neuroectodermal cells, may share protein synthesis and regulation pathways that become dysfunctional in PD and melanoma.