Genotype-phenotype correlations of amyotrophic lateral sclerosis

Li, Hongfu; Wu, Zhi‐Ying

doi:10.1186/s40035-016-0050-8

Cited by 79 publications

(68 citation statements)

References 127 publications

(144 reference statements)

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“…Indeed, twin studies revealed that each of the major phenotypes associated with neurofibromatosis type 1 is affected by distinct modifiers (Easton et al, 1993), none of which have yet been identified. This feature, along with the natural history of this complex disease and the relatively small number of recurrent mutations has precluded identification of clear genotype-phenotype correlations (Li and Wu, 2016). Recent psychiatric analysis of neurofibromatosis type 1 patients revealed that the NF1 gene functions as a quantitative trait locus that is associated with autism spectrum disorders (ASD) (Morris et al, 2016).…”

Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,465

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,465

1,350

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“…Variations of more than 30 genes have been associated with sporadic ALS, but these variations have not been linked to specific environmental risk factors, though epigenetics is a new area that is ripe for investigation [18]. The alteration of gene expression through DNA methylation, histone modification, and non-coding RNA-associated gene silencing are all targets of environmental insults considered to induce and sustain epigenetic changes that might result in neurodegeneration.…”

Section: Gene-environment Interactions In Alsmentioning

confidence: 99%

Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

et al. 2018

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Background: Amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s diseases are age-related neurodegenerative diseases. ALS is not a single entity but a syndrome with many different causes. In all 3 diseases, gene mutations account for only 10–15% of cases. Many environmental and lifestyle factors have been implicated as risk factors for ALS, though none have been proven to cause the disease. It is generally believed that ALS results from interactions between environmental risk factors and genetic predisposing factors. The advent of next-generation sequencing and recent advances in research into environmental risk factors offer the opportunity to investigate these interactions. Summary: We propose a hypothesis to explain the syndrome of ALS based on the interaction of many individual environmental risk factors with many individual genetic predisposing factors. We hypothesize that there are many such combinations of individual, specific, genetic, and environmental factors, and that each combination can lead to the development of the syndrome of ALS. We also propose a hypothesis that explains the overlap between the age-related neurodegenerations and their genetic underpinnings. Age and duration of exposure are crucial factors in these age-related neurodegenerative diseases, and we consider how these may relate to gene-environment interactions. Key Messages: To date, genetic studies and environmental studies have investigated the causes of ALS separately. We argue that this univariate approach will not lead to discoveries of important gene-environment interactions. We propose new research approaches to investigating gene-environment interactions based on these hypotheses.

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“…4 Since 1993, when the superoxide dismutase 1 (SOD1) gene was found to be mutated in fALS patients, an increasing number of disease genes, designated ALS 1-22, have been reported. 5 In 2009, ALS11 was identified as a rare autosomal dominant form of ALS associated with heterozygous deleterious variants of FIG4 in North American patients. 6 FIG4 encodes a phosphoinositide 5-phosphatase regulating phosphatidylinositol-3,5-bisphosphate, an intracellular signaling lipid with a key role in endosomal vesicle trafficking.…”

Section: Introductionmentioning

confidence: 99%

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

et al. 2017

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We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization to explore genotype-phenotype relationships. WES analysis of the ALS family identified the rare heterozygous frameshift variant FIG4:c.759delG, p.(F254Sfs*8) predicted to delete the catalytic domain and active center from the encoded phosphoinositide 5-phosphatase with a key role in endosomal vesicle trafficking. Additionally, novel or rare heterozygous FIG4 missense variants predicted to be deleterious were detected in five sporadic ALS patients revealing an overall FIG4 variant frequency of 3% in our cohort. Four of six variants identified were previously associated with ALS or the motor and sensory neuropathy Charcot-Marie-Tooth disease type 4J (CMT4J), whereas two variants were novel. In FIG4 variant carriers, disease duration was longer and upper motor neuron predominance was significantly more frequent compared with ALS patients without FIG4 variants. Our study provides evidence for FIG4 as an ALS risk gene in a central European cohort, adds new variants to the mutational spectrum, links ALS to CMT4J on a genetic level, and describes a distinctive ALS phenotype for FIG4 variant carriers.

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Genotype-phenotype correlations of amyotrophic lateral sclerosis

Cited by 79 publications

References 127 publications

RAS Proteins and Their Regulators in Human Disease

RAS Proteins and Their Regulators in Human Disease

Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

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