Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis

Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p=0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06-2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p=0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09-4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16-4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis.     

VCP mutations in familial and sporadic amyotrophic lateral sclerosis

Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.     

TP53 Arg72Pro polymorphism in Turkish patients with sporadic amyotrophic lateral sclerosis

Recently, Eve et al. (2007) reported that the expression of TP53 (NM_000546) was increased by 2.1-fold in whole spinal cord and 2.7-fold in the ventral horn of amyotrophic lateral sclerosis (ALS) patients. Based on this particular observation, we decided to evaluate whether the TP53 Arg72Pro polymorphism (rs1042522) (C215G) was implicated in the etiopathology of sporadic amyotrophic lateral sclerosis (SALS). Therefore, we genotyped 394 Turkish SALS patients and 439 matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We did not find any association between overall SALS patients with the TP53 Arg72Pro polymorphism and controls (χ² = 2.674; p = 0.263). Consequently the TP53 Arg72Pro polymorphism was not associated with SALS.     

Lack of association between angiotensin converting enzyme polymorphism and sporadic Alzheimer's disease

Epidemiological and pathogenetic evidences suggest a strong association between vascular risk factors and sporadic Alzheimer's disease (sAD). In agreement with the vascular hypothesis of AD, the role of various candidate genes for atherosclerosis has been investigated, leading to conflicting results. In order to clarify the significance of angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism in a group of patients with sAD, we conducted a case-control study including 149 cases and 149 age and sex matched controls. All subjects were genotyped for ACE and Apolipoprotein E (APOE). There were no significant differences in ACE genotype or allele frequencies between cases and controls, even after stratification for APOE4 carrier status. Our data suggest that the ACE I/D polymorphism is not associated to genetic susceptibility in sAD patients.     

Novel optineurin mutations in sporadic amyotrophic lateral sclerosis patients

Optineurin (OPTN) mutations have been reported in a cohort of Japanese patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis. In Caucasian patients, OPTN mutations have been identified in FALS patients, but were not detected in a cohort of 95 SALS patients. Moreover, single nucleotide polymorphisms (SNPs) in OPTN that could raise amyotrophic lateral sclerosis (ALS) susceptibility have not been investigated. Therefore, we screened a large Dutch cohort of 1191 patients with SALS, 94 patients with FALS, and 1415 control subjects for mutations and SNPs in OPTN. We identified 1 novel nonsense mutation (Q165X) and 1 unreported missense mutation (Q454E) in individual SALS patients. These patients demonstrated rapid disease progression with an average survival of 24.5 months. No heterozygous or homozygous OPTN mutations were identified in our cohort of FALS patients. SNP analysis did not reveal significant differences between ALS patients and control subjects. Therefore, variations in OPTN appear to be a rare cause of rapidly progressive SALS in the Netherlands.     

No association between DNA repair gene XRCC1 and amyotrophic lateral sclerosis

Reduced DNA repair capacity may play a role in amyotrophic lateral sclerosis (ALS) etiology. We examined the association between ALS risk and single nucleotide polymorphisms (SNPs) in the gene x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) utilizing data from a case-control study and 2 genome-wide association studies (the study of Irish Amyotrophic Lateral Sclerosis and the National Institute of Neurological Disorders and Stroke (NINDS) genome-wide study in Amyotrophic Lateral Sclerosis and Neurologically Normal Controls). Our results did not show any differences in the frequency of XRCC1 gene polymorphisms between ALS patients and controls free of any neurological disease.     

Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis

Background  

Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood.     

Hypotheses to explain the association between vigorous physical activity and amyotrophic lateral sclerosis

Many epidemiologic studies indicate a relation between vigorous physical activity and amyotrophic lateral sclerosis. Physical activity itself is unlikely to cause amyotrophic lateral sclerosis, but could it modify the effects of other etiologic factors such as neurotoxins? Vigorous physical activity could potentiate the effect of a toxin to motor neurons by any of several mechanisms, especially if the toxin's effects were mediated through excitation. Exercise could alter the extent of exposure or could influence the distribution, metabolism or potency of an excitotoxin. Future epidemiologic studies of amyotrophic lateral sclerosis should include sufficient detail about vigorous physical exercise to explore this relationship further.     

Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia

Mutations in the profilin 1 (PFN1) gene, encoding a protein regulating filamentous actin growth through its binding to monomeric G-actin, have been recently identified in familial amyotrophic lateral sclerosis (ALS). Functional studies performed on ALS-associated PFN1 mutants demonstrated aggregation propensity, alterations in growth cone, and cytoskeletal dynamics. Previous screening of PFN1 gene in sporadic ALS (SALS) cases led to the identification of the p.E117G mutation, which is likely to represent a less pathogenic variant according to both frequency data in control subjects and cases, and functional experiments. To determine the effective contribution of PFN1 mutations in SALS, we analyzed a large cohort of 1168 Italian SALS patients and also included 203 frontotemporal dementia (FTD) cases because of the great overlap between these 2 neurodegenerative diseases. We detected the p.E117G variant in 1 SALS patient and the novel synonymous change p.G15G in another patient, but none in a panel of 1512 control subjects. Our results suggest that PFN1 mutations in sporadic ALS and in FTD are rare, at least in the Italian population.     

Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the motor cortex, brain stem and spinal cord. Mutations in the valosin-containing protein gene (VCP) were recently described in ALS families. Some of these families included diagnoses of other clinical features including frontotemporal dementia, Paget's disease, inclusion body myopathy, Parkinsonism and limb weakness. We sought to determine the prevalence of VCP mutations in Australian familial (n = 131) and sporadic (n = 48) ALS cohorts diagnosed with classic ALS. No mutations were identified indicating that VCP mutations are not a common cause of classic ALS among Australian cases with predominantly European ancestry.     

Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis

Mutations in PFN1, a gene encoding the actin monomer-binding protein profilin 1, were recently reported in 1% to 2% of familial amyotrophic lateral sclerosis (ALS) patients. In vitro functional studies suggested that PFN1 mutations lead to ubiquitin-positive inclusions and impairment of cytoskeletal pathways. In the present study, mutation analysis of PFN1 was performed in an Australian cohort of 110 ALS families and 715 sporadic ALS patients. No PFN1 mutations were identified in familial ALS patients. Two rare non-synonymous variants (E117D and E117G) were found in sporadic ALS patients at similar incidences to that reported in public SNP databases. Immunostaining of PFN1 in sporadic ALS and familial ALS patients, including those with mutations in SOD1, FUS, UBQLN2 and C9ORF72, found no PFN1-positive inclusions in spinal motor neurons. Our data suggest that PFN1 mutations and pathology are not common in an Australian ALS cohort of predominantly European ancestry.     

Lack of association between the CYP46 gene polymorphism and Italian late-onset sporadic Alzheimer's disease

Recent studies have provided evidence toward the possible involvement of brain cholesterol homeostasis in late-onset Alzheimer's disease (LOAD). We analyzed an intronic T-->C substitution (rs 754203) of the cholesterol 24S-hydroxylase (CYP46) gene, encoding an enzyme acting on brain cholesterol turnover, which has been recently associated with an increased risk of AD, dependent or not on Apolipoprotein E (ApoE) genotype. No significant association was found for the CYP46 polymorphism in LOAD compared to the controls, even after stratification for the presence/absence of the ApoE*4 allele. Our data do not support a role of the CYP46 polymorphism as a possible susceptibility factor for developing AD.     

An explanation for the changes in collagen in sporadic amyotrophic lateral sclerosis

There is evidence showing abnormalities in collagen from the skin of patients with sporadic Amyotrophic Lateral Sclerosis (sALS) both from Guam and elsewhere. The non-proteinogenic amino acid beta-N-methylamino-l-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-proteinogenic amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. We hypothesize that the abnormalities seen in sALS collagen may result from the misincorporation of BMAA and subsequent misfolding of the collagen protein.     

Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis

We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for <1% of this form of disease.     

FUS mutations in sporadic amyotrophic lateral sclerosis: clinical and genetic analysis

Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3'-untranslated region [UTR] variant, c.*41G>A; c.523+3ins[GAGGTG]; c.335-15del[TTTT]; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes.     

A genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations

Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease that causes progressive motor neuron death. Although the etiology of sALS remains unknown, genetic variants are thought to predispose individuals to the disease. Several recent genome-wide association studies have identified a number of loci that increase sALS susceptibility, but these only explain a small proportion of the disease. To extend the current genetic evidence and to identify novel candidates of sALS, we performed a pooling genome-wide association study by 859,311 autosomal single-nucleotide polymorphisms of IlluminaHumanOmniZhongHua-8 combining pathway analysis in 250 typical sALS cases precluding age, clinical course, and phenotype interference and 250 control subjects from Chinese Han populations (CHP). The results revealed that 8 novel loci of 1p34.3, 3p21.1, 3p22.2, 10p15.2, 22q12.1, 3q13.11, 11q25, 12q24.33, and 5 previously reported loci of CNTN4 (kgp11325216), ATXN1 (kgp8327591), C9orf72 (kgp6016770), ITPR2 (kgp3041552), and SOD1 (kgp10760302) were associated with sALS from CHP. Furthermore, the pathway analysis based on the Gene Set Analysis Toolkit V2 showed that 10 top pathways were strongly associated with sALS from CHP, and among them, the 7 most potentially candidate pathways were phosphatidylinositol signaling system, Wnt signaling pathway, axon guidance, MAPK signaling pathway, neurotrophin signaling pathway, arachidonic acid metabolism, and T-cell receptor signaling pathway, a total of 39 significantly associate genes in 7 candidate pathways was suggested to involve in the pathogenesis of sALS from CHP. In conclusion, our results revealed several new loci and pathways related to sALS from CHP and extend the association evidence for partial loci, genes, and pathways, which were previously identified in other populations. Thus, our data provided new clues for exploring the pathogenesis of sALS.