scholarly journals Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

2020 ◽  
pp. jmedgenet-2020-106866 ◽  
Author(s):  
Emily P McCann ◽  
Lyndal Henden ◽  
Jennifer A Fifita ◽  
Katharine Y Zhang ◽  
Natalie Grima ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Variation ◽  
Genetic Analysis ◽  
Genetic Variants ◽  
Age Of Onset ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Whole Genome ◽  
Identity By Descent ◽  
Sporadic Als ◽  
Lateral Sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.

scholarly journals Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

2021 ◽  
Vol 49 (7) ◽  
pp. 030006052110332
Author(s):  
Zhiliang Fan ◽  
Hong Jiang ◽  
Xueqin Song ◽  
Yansu Guo ◽  
Xinying Tian
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Healthy Subjects ◽  
Chinese Population ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Glutathione S Transferase ◽  
Genotype Frequencies ◽  
Sporadic Als ◽  
Increased Risk ◽  
Chi Squared ◽  
Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

scholarly journals FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis

2012 ◽  
Vol 33 (4) ◽  
pp. 837.e1-837.e5 ◽  
Author(s):  
William Sproviero ◽  
Vincenzo La Bella ◽  
Rosalucia Mazzei ◽  
Paola Valentino ◽  
Carmelo Rodolico ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Analysis ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

scholarly journals SMN1 copy number as a modifying factor of survival in Serbian patients with sporadic amyotrophic lateral sclerosis

2018 ◽  
Vol 146 (11-12) ◽  
pp. 646-652
Author(s):  
Milos Brkusanin ◽  
Irena Jeftovic-Velkova ◽  
Vladimir Jovanovic ◽  
Stojan Peric ◽  
Jovan Pesovic ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Copy Number ◽  
Rating Scale ◽  
Cox Regression ◽  
Diagnostic Delay ◽  
Susceptibility Genes ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Cox Regression Analysis ◽  
Sporadic Als ◽  
Lateral Sclerosis

Introduction/Objective. Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The majority of cases are apparently sporadic ALS (SALS) with variants in susceptibility genes or sometimes in high-risk ALS genes. Two ALS susceptibility genes are SMN1, whose functional loss causes spinal muscular atrophy (SMA), and a nearly identical SMN2 gene, which modulates SMA severity. In this study we examined the association of copy number variations (CNVs) of SMN1 and SMN2 genes and two additional genes, SERF1 and NAIP, residing in the same genomic region (i.e. 5q13.2 segmental duplication), with SALS in patients from Serbia. Methods. Multiplex ligation-dependent probe amplification was used to determine CNVs of each gene in a clinically well-characterised group of 153 Serbian SALS patients and 153 controls. Results. Individual association between SMN1, SMN2, SERF1 or NAIP CNVs and SALS susceptibility or survival was not found. Survival curves based on the multivariable Cox regression analysis showed that three SMN1 copies, lower ALS Functional Rating Scale Revised (ALSFRS-R) score at the time of diagnosis, faster decline of the ALSFRS-R score over time, and shorter diagnostic delay result in shorter survival of Serbian SALS patients. Conclusion. Clinical variables might be complemented with the SMN1 copy number to improve prediction of survival in Serbian SALS patients.

Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis

2009 ◽  
Vol 19 (10) ◽  
pp. 696-700 ◽  
Author(s):  
Natasha Luquin ◽  
Bing Yu ◽  
Rebecca B. Saunderson ◽  
Ronald J. Trent ◽  
Roger Pamphlett
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Variants ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

2011 ◽  
Vol 6 (1) ◽  
Author(s):  
Gisella Gargiulo Monachelli ◽  
Maria Meyer ◽  
Gabriel Rodríguez ◽  
Laura Garay ◽  
Roberto E. Sica ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Prognostic Factors ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Sporadic Als ◽  
Bulbar Onset ◽  
Als Patients ◽  
Short Time ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center

2016 ◽  
Vol 18 (3-4) ◽  
pp. 249-255 ◽  
Author(s):  
Gerson Chadi ◽  
Jessica Ruivo Maximino ◽  
Frederico Mennucci de Haidar Jorge ◽  
Fabrício Castro de Borba ◽  
Joyce Meire Gilio ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Analysis ◽  
Research Center ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Sandrine Chan Moi Fat ◽  
Emily P. McCann ◽  
Kelly L. Williams ◽  
Lyndal Henden ◽  
Natalie A. Twine ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Analysis ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis

scholarly journals Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 159 ◽  
Author(s):  
Valentina La Cognata ◽  
Giulia Gentile ◽  
Eleonora Aronica ◽  
Sebastiano Cavallaro
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Interactions ◽  
Brain Regions ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Splicing Factors ◽  
Granule Formation ◽  
Disease States ◽  
Sporadic Als ◽  
Genes Encoding ◽  
Lateral Sclerosis

Splicing is a tightly orchestrated process by which the brain produces protein diversity over time and space. While this process specializes and diversifies neurons, its deregulation may be responsible for their selective degeneration. In amyotrophic lateral sclerosis (ALS), splicing defects have been investigated at the singular gene level without considering the higher-order level, involving the entire splicing machinery. In this study, we analyzed the complete spectrum (396) of genes encoding splicing factors in the motor cortex (41) and spinal cord (40) samples from control and sporadic ALS (SALS) patients. A substantial number of genes (184) displayed significant expression changes in tissue types or disease states, were implicated in distinct splicing complexes and showed different topological hierarchical roles based on protein–protein interactions. The deregulation of one of these splicing factors has a central topological role, i.e., the transcription factor YBX1, which might also have an impact on stress granule formation, a pathological marker associated with ALS.

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