Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
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ABSTRACT:
SUBMITTER: Chow CY
PROVIDER: S-EPMC2668033 | biostudies-literature | 2009 Jan
REPOSITORIES: biostudies-literature
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Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
Chow Clement Y CY Landers John E JE Bergren Sarah K SK Sapp Peter C PC Grant Adrienne E AE Jones Julie M JM Everett Lesley L Lenk Guy M GM McKenna-Yasek Diane M DM Weisman Lois S LS Figlewicz Denise D Brown Robert H RH Meisler Miriam H MH
American journal of human genetics 20090101 1
Mutations of the lipid phosphatase FIG4 that regulates PI(3,5)P(2) are responsible for the recessive peripheral-nerve disorder CMT4J. We now describe nonsynonymous variants of FIG4 in 2% (9/473) of patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Heterozygosity for a deleterious allele of FIG4 appears to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases. ...[more]
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Project description:ObjectiveThe aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region.MethodsWe used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains.ResultsA homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations.ConclusionsThis study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.
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| S-EPMC3644641 | biostudies-literature
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| S-EPMC6467804 | biostudies-literature
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| S-EPMC6030899 | biostudies-literature
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| S-EPMC5389506 | biostudies-literature