Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice DOI Creative Commons
Ikuo Ogiwara, Hiroyuki Miyamoto, Tetsuya Tatsukawa

et al.

Communications Biology, Journal Year: 2018, Volume and Issue: 1(1)

Published: July 13, 2018

Mutations in the SCN2A gene encoding a voltage-gated sodium channel Nav1.2 are associated with epilepsies, intellectual disability, and autism. gain-of-function mutations cause early-onset severe while loss-of-function autism milder and/or later-onset epilepsies. Here we show that both heterozygous Scn2a-knockout knock-in mice harboring patient-derived nonsense mutation exhibit ethosuximide-sensitive absence-like seizures spike-and-wave discharges at adult stages. Unexpectedly, identical reproduced even more prominent Scn2a deletion specifically dorsal-telencephalic (e.g., neocortical hippocampal) excitatory neurons, but undetected selective inhibitory neurons. In cerebral cortex of wild-type mice, most is expressed neurons steady increase redistribution from proximal (i.e., axon initial segments) to distal axons. These results indicate pivotal role haplodeficiency epilepsies patients mutations.

Language: Английский

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism DOI Creative Commons
F. Kyle Satterstrom,

Jack A. Kosmicki,

Jiebiao Wang

et al.

Cell, Journal Year: 2020, Volume and Issue: 180(3), P. 568 - 584.e23

Published: Jan. 23, 2020

Language: Английский

Citations

1898
Neurodevelopmental disorders—the history and future of a diagnostic concept DOI Creative Commons
Deborah J. Morris‐Rosendahl,

Marc-Antoine Crocq

Dialogues in Clinical Neuroscience, Journal Year: 2020, Volume and Issue: 22(1), P. 65 - 72

Published: March 31, 2020

This article describes the history of diagnostic class neurodevelopmental disorders (NDDs) up to DSM-5. We further analyze how development genetics will transform classification and diagnosis NDDs. In DSM-5, NDDs include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity (ADHD). Physicians in German-, French- English-speaking countries (eg, Weikard, Georget, Esquirol, Down, Asperger, Kanner) contributed phenomenological definitions these throughout 18th 20th centuries. These categories show considerable comorbidity phenotypic overlap. are one chapters psychiatric nosology most likely benefit from approach advocated by National Institute Mental Health's Research Domain Criteria project. Genetic research supports hypothesis that ID, ASD, ADHD, schizophrenia, bipolar lie on a continuum. The identification recurrently observed copy number variants disruptive gene ASD CDH8, 16p11.2, SCN2A) led adoption genotype-first characterize individuals at etiological level.

Language: Английский

Citations

326
Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder DOI Open Access
Joon‐Yong An, Kevin Lin, Lingxue Zhu

et al.

Science, Journal Year: 2018, Volume and Issue: 362(6420)

Published: Dec. 14, 2018

INTRODUCTION The DNA of protein-coding genes is transcribed into mRNA, which translated proteins. “coding genome” describes the that contains information to make these proteins and represents ~1.5% human genome. Newly arising de novo mutations (variants observed in a child but not either parent) coding genome contribute numerous childhood developmental disorders, including autism spectrum disorder (ASD). Discovery effects aided by triplet code enables functional impact many be readily deciphered. In contrast, “noncoding covers remaining ~98.5% includes elements regulate when, where, what degree are transcribed. Understanding this noncoding sequence could provide insights disorders refined control emerging genetic therapies. Yet little known about role regions, whether they most vulnerable disruption, manner encoded RATIONALE Whole-genome sequencing (WGS) provides opportunity identify majority variation each individual. By performing WGS on 1902 quartet families affected with ASD, one unaffected sibling control, their parents, we identified ~67 across child’s To characterize mutations, integrated multiple datasets relating gene function, implicated neurodevelopmental conservation species, epigenetic markers, thereby combinatorially defining 55,143 categories. scope problem—testing for an excess cases relative controls category—is challenging because there more categories than families. RESULTS Comparing controls, individual overcome challenge detecting association, used machine learning tools develop risk score look This demonstrated contribution ASD from weaker, significant, mutations. signal was driven promoter region, defined as 2000 nucleotides upstream transcription start site (TSS) where mRNA synthesis starts. strongest signals were species factor binding sites. Well-defined (e.g., TATA-box) usually within 80 TSS; however, association distally, 750 TSS. CONCLUSION We conclude ASD. clearest evidence came at evolutionarily conserved region. enrichment sites, primarily distal promoter, suggests may disrupt via interaction enhancer rather interfering transcriptional initiation directly. Promoter regions autism. De assigned annotation categories, assessed (ASD) comparing mutation counts controls. A especially sites or targeted factors.

Language: Английский

Citations

303
Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies DOI Open Access

Julia Oyrer,

Snezana Maljevic, Ingrid E. Scheffer

et al.

Pharmacological Reviews, Journal Year: 2017, Volume and Issue: 70(1), P. 142 - 173

Published: Dec. 20, 2017

Epilepsy is a common and serious neurologic disease with strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact these discoveries wide reaching—from precise diagnosis classification syndromes to the discovery validation new drug targets development disease-targeted therapeutic strategies. About 25% genes in epilepsy encode ion channels. Much our understanding mechanisms comes from work focused on this class protein. In study, we review genetic, molecular, physiologic evidence supporting pathogenic role number different voltage- ligand-activated channels epilepsy. We also proposed for each channel highlight targeted

Language: Английский

Citations

271
Progress in Understanding and Treating SCN2A-Mediated Disorders DOI Creative Commons
Stephan Sanders, Arthur J. Campbell,

Jeffrey R. Cottrell

et al.

Trends in Neurosciences, Journal Year: 2018, Volume and Issue: 41(7), P. 442 - 456

Published: April 23, 2018

Language: Английский

Citations

266
Molecular basis for pore blockade of human Na + channel Na v 1.2 by the μ-conotoxin KIIIA DOI Open Access
Xiaojing Pan, Zhangqiang Li, Xiaoshuang Huang

et al.

Science, Journal Year: 2019, Volume and Issue: 363(6433), P. 1309 - 1313

Published: Feb. 15, 2019

Targeting sodium channels Voltage-gated (Na v ) have been implicated in cardiac and neurological disorders. There are many subtypes of these channels, making it challenging to develop specific therapeutics. A core α subunit is sufficient for voltage sensing ion conductance, but function modulated by β subunits natural toxins that can either act as pore blockers or gating modifiers (see the Perspective Chowdhury Chanda). Shen et al. present structures Na 1.7 complex with both β1 β2 animal toxins. Pan structure 1.2 bound a toxic peptide, µ-conotoxin KIIIA. The shows why KIIIA 1.2. These other recently determined provide framework targeted drug development. Science , this issue p. 1303 1309 ; see also 1278

Language: Английский

Citations

241
The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex DOI Creative Commons

Perry W.E. Spratt,

Roy Ben‐Shalom,

Caroline M. Keeshen

et al.

Neuron, Journal Year: 2019, Volume and Issue: 103(4), P. 673 - 685.e5

Published: June 20, 2019

Language: Английский

Citations

195
Genomics, convergent neuroscience and progress in understanding autism spectrum disorder DOI
Helen Rankin Willsey, A. Jeremy Willsey, Belinda Wang

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(6), P. 323 - 341

Published: April 19, 2022

Language: Английский

Citations

144
Sodium channelopathies in neurodevelopmental disorders DOI
Miriam H. Meisler, Sophie F. Hill, Wenxi Yu

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 22(3), P. 152 - 166

Published: Feb. 2, 2021

Language: Английский

Citations

136
Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders DOI Creative Commons
Marlen C. Lauffer, Willeke M. C. van Roon‐Mom, Annemieke Aartsma‐Rus

et al.

Communications Medicine, Journal Year: 2024, Volume and Issue: 4(1)

Published: Jan. 5, 2024

Abstract Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts slow down or halt rare genetic disease progression. They offer the potential groups of patients tailored for individual cases. Nonetheless, not all variants disorders amenable ASO-based treatments, hence, it is important consider several factors before embarking on drug development journey. Here, we discuss which have benefit from a specific type ASO approach, based pathophysiology pathogenic variant type, as well those might suitable therapies. We further explore additional aspects, such tissues, intervention time points, clinical benefits, need considered developing compound. Overall, provide an overview current potentials limitations therapeutics treatment monogenic disorders.

Language: Английский

Citations

86