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Abstract
Objective: The 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.
Methods: We 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.
Results: A 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.
Conclusions: This 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.
GLOSSARY
- cDNA=
- complementary DNA;
- chr6=
- chromosome 6;
- CMT4J=
- Charcot-Marie-Tooth disease type 4J;
- GFP=
- green fluorescent protein;
- plt=
- pale tremor;
- WT=
- wild-type;
- YVS=
- Yunis-Varón syndrome
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Supplemental data at Neurology.org
- Received July 10, 2013.
- Accepted in final form December 12, 2013.
- © 2014 American Academy of Neurology
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