PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

JCI Insight, Journal Year: 2016, Volume and Issue: 1(9)

Published: June 15, 2016

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent next-generation sequencing (NGS). Mosaic mutations PIK3CA have been associated widest spectrum phenotypes overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes amplicon in cohort 241 samples from 181 individuals brain and/or body overgrowth. identified 60 individuals. Several other (n = 12) were separately to by clinical targeted-panel testing 6), whole-exome 5), or Sanger 1). Based on features, this segregated into three distinct groups: (a) severe focal due low-level but highly activating (hotspot) mutations, (b) predominantly less somatic less-activating (c) intermediate (capillary malformations overgrowth) intermediately mutations. Sixteen 29 novel. also constitutional 10 patients. Our data, combined review literature, show PIK3CA-related comprise discontinuous correlate severity distribution

Language: Английский

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PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(12), P. 3725 - 3725

Published: Nov. 23, 2018

Phosphoinositide 3-kinase (PI3K) signaling contributes to a variety of processes, mediating many aspects cellular function, including nutrient uptake, anabolic reactions, cell growth, proliferation, and survival. Less is known regarding its critical role in neuronal physiology, metabolism, tissue homeostasis, the control gene expression central nervous system healthy diseased states. The aim present work review cumulative evidence participation PI3K pathways focusing on their metabolism transcriptional regulation genes involved maintenance plasticity or pathological hallmarks associated with neurodegeneration.

Language: Английский

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Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Epilepsia, Journal Year: 2016, Volume and Issue: 57(6), P. 994 - 1003

Published: May 13, 2016

Summary Objective The discovery of mutations in DEPDC 5 familial focal epilepsies has introduced a novel pathomechanism to field so far dominated by ion channelopathies. is part complex named GAP activity toward RAGs (GATOR) 1 ( GATOR 1), together with the proteins NPRL 2 and 3, acts inhibit mechanistic target rapamycin mTOR ) mTORC 1) pathway. turn inhibited complex. pathway major signaling cascade regulating cell growth, proliferation, migration. We aimed study contribution genes etiology describe associated phenotypical spectrum. Methods performed targeted sequencing encoding components 5, 2, 3) MIOS , SEC 13, SEH 1L, WDR 24, 59 93 European probands epilepsy or without cortical dysplasia. Phospho‐S6 immunoreactivity was used as evidence activation resected brain tissue patients carrying pathogenic variants. Results identified four variants two one 3 . showed hyperactivation from mutations. Collectively, inactivating explained 11% cases whereas no were found genes. 1‐related differ clinically due channel their association dysplasia seizures emerging variable foci, might confer an increased risk sudden unexplained death SUDEP ). Significance gene leading upregulation important cause malformations represents potential for therapeutic approaches.

Language: Английский

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Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

Cell Reports, Journal Year: 2018, Volume and Issue: 22(8), P. 2080 - 2093

Published: Feb. 1, 2018

Microglia are well known to play a critical role in maintaining brain homeostasis. However, their epileptogenesis has yet be determined. Here, we demonstrate that elevated mTOR signaling mouse microglia leads phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without significant induction of pro-inflammatory cytokines. We further provide evidence these noninflammatory changes disrupt homeostasis the CNS, leading reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, massive proliferation astrocytes. Moreover, mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, have revealed epileptogenic mechanism is independent inflammatory response. Our data suggest could opportune target for epilepsy prevention.

Language: Английский

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Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases

Journal of Molecular Neuroscience, Journal Year: 2016, Volume and Issue: 61(3), P. 379 - 384

Published: Dec. 26, 2016

Neurodevelopmental biology, coupled with the application of advanced histological, imaging, molecular, cellular, biochemical, and genetic approaches, has provided new insights into these intricate genetic, molecular events. During telencephalic development, specific neural progenitor cells (NPCs) proliferate, differentiate numerous cell types, migrate to their apposite positions, form an integrated circuitry. Critical disturbance this dynamic process via environmental risk can cause neurological disorders disability. The phosphatidylinositol-3-OH kinase (PI3K)-Akt-mammalian target rapamycin (mTOR) signaling cascade contributes mediate various cellular processes, including proliferation growth, nutrient uptake. In light its critical function, dysregulation node been regarded as a root several neurodevelopmental diseases, such megalencephaly ("big brain"), microcephaly ("small autism spectrum disorders, intellectual disability, schizophrenia, epilepsy. review, particular emphasis will be given PI3K-Akt-mTOR pathway paramount importance in neurodevelopment cerebral neocortex, because roles complex cognition, emotional regulation, language, behaviors.

Language: Английский

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