Role of the phosphoinositide phosphatase
            <i>FIG4</i>
            gene in familial epilepsy with polymicrogyria

Baulac, Stéphanie; Lenk, Guy M.; Dufresnois, Béatrice; Bencheikh, Bouchra Ouled Amar; Couarch, Philippe; Renard, Julie; Larson, Peter A.; Ferguson, Cole; Noé, Eric; Poirier, Karine; Hubans, Christine; Ferreira, Stéphanie; Guerrini, Renzo; Ouazzani, R.; Hachimi, Khalid Hamid El; Meisler, Miriam H.; LeGuern, Eric

doi:10.1212/wnl.0000000000000241

Cited by 102 publications

(50 citation statements)

References 26 publications

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“…9 Biallelically mutated FIG4 was detected in patients with (i) Charcot-Marie-Tooth disease type 4J (CMT4J), 9 a recessively inherited form of hereditary motor and sensory neuropathy, (ii) Yunis-Varón syndrome, 10 an autosomal recessive disorder with skeletal anomalies and severe neurological involvement, and (iii) familial epilepsy with polymicrogyria. 11 Here, we present known and novel heterozygous deleterious FIG4 variants in a cohort of 201 central European fALS and sALS patients, and provide clinical, electrophysiological, and neuroradiological information on FIG4 variant carriers.…”

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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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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“…15 Mutations of FIG4 result in recessive neurological disorders, including the peripheral neuropathy Charcot-Marie-Tooth type 4J (MIM: 611228), the multisystem disorder Yunis-Varón syndrome (MIM: 216340), and polymicrogyria with seizures and psychiatric co-morbidities (MIM: 612691). [15][16][17][18] Haploinsufficiency of PIKFYVE results in the benign condition fleck corneal dystrophy (MIM: 121850) with accumulation of intracytoplasmic vesicles. 19 Pathogenic mutations of human VAC14, which is located on chromosome 16q22, have not previously been reported.…”

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Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Lenk

Sztefko

Dębska–Vielhaber

et al. 2016

The American Journal of Human Genetics

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In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.

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“…3). Mutations in FIG4, the gene that encodes a positive regulator of PI(3,5)P 2 (4)(5)(6)(7)(8)(9)(10), are linked to several neurological disorders, including Charcot-Marie-Tooth type 4J (CMT4J) (4,11), ALS, and primary lateral sclerosis (12), familial epilepsy with polymicrogyria (13) and Yunis-Varón syndrome (14). Little is known about how perturbations in PI(3,5)P 2 synthesis cause disease.…”

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Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression

McCartney

Zolov²,

Kauffman³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ], because mutations in PI(3,5)P 2 -related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P 2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type. Notably, the mammalian homolog of yeast vacuole segregation mutant (Vac14), a scaffold for the PI(3,5)P 2 synthesis complex, is concentrated at excitatory synapses, suggesting a potential role for PI(3,5)P 2 in controlling synapse function and/or plasticity. PI(3,5)P 2 is generated from phosphatidylinositol 3-phosphate (PI3P) by the lipid kinase PI3P 5-kinase (PIKfyve). Here, we present methods to measure and control PI(3,5)P 2 synthesis in hippocampal neurons and show that changes in neural activity dynamically regulate the levels of multiple PIPs, with PI(3,5)P 2 being among the most dynamic. The levels of PI(3,5)P 2 in neurons increased during two distinct forms of synaptic depression, and inhibition of PIKfyve activity prevented or reversed induction of synaptic weakening. Moreover, altering neuronal PI(3,5)P 2 levels was sufficient to regulate synaptic strength bidirectionally, with enhanced synaptic function accompanying loss of PI(3,5)P 2 and reduced synaptic strength following increased PI(3,5)P 2 levels. Finally, inhibiting PI(3,5)P 2 synthesis alters endocytosis and recycling of AMPA-type glutamate receptors (AMPARs), implicating PI(3,5)P 2 dynamics in AMPAR trafficking. Together, these data identify PI(3,5)P 2 -dependent signaling as a regulatory pathway that is critical for activity-dependent changes in synapse strength.PIKfyve | Fab1 | phosphatidylinositol lipids | synaptic plasticity | Vac14 P hosphorylated phosphoinositide lipids (PIPs) regulate diverse cellular processes (reviewed in refs. 1, 2). These seven interconvertible PIP species are synthesized and turned over by highly regulated lipid kinases and phosphatases. PIPs likely assemble complex protein machines on membrane subdomains through binding of specific downstream protein effectors, which provides tight spatial and temporal control of cellular processes. Such precision is likely critical for complex cellular functions, including regulation of synaptic strength in the CNS.Pleiotropic defects are associated with impairments in phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ] synthesis (reviewed in ref.3). Mutations in FIG4, the gene that encodes a positive regulator of PI(3,5)P 2 (4-10), are linked to several neurological disorders, including Charcot-Marie-Tooth type 4J (CMT4J) (4, 11), ALS, and primary lateral sclerosis (12), familial epilepsy with polymicrogyria (13) and Yunis-Varón syndrome (14). Little is known about how pert...

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Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria

Abstract: 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.

Cited by 102 publications

References 26 publications

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

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

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression

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Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria

Abstract: 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.

Cited by 102 publications

References 26 publications

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

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

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Activity-dependent PI(3,5)P 2 synthesis controls AMPA receptor trafficking during synaptic depression

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Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression