Dataset Information

Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.

ABSTRACT: Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.

SUBMITTER: Negraes PD

PROVIDER: S-EPMC8531162 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.

Negraes Priscilla D PD Trujillo Cleber A CA Yu Nam-Kyung NK Wu Wei W Yao Hang H Liang Nicholas N Lautz Jonathan D JD Kwok Ellius E McClatchy Daniel D Diedrich Jolene J de Bartolome Salvador Martinez SM Truong Justin J Szeto Ryan R Tran Timothy T Herai Roberto H RH Smith Stephen E P SEP Haddad Gabriel G GG Yates John R JR Muotri Alysson R AR

Molecular psychiatry 20210422 11

Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protei ...[more]

PMID: 33888873

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Project description:ImportanceAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.ObjectivesTo assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.Design, setting, and participantsIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020.ExposuresRare and novel variants categorized as pathogenic or likely pathogenic.Main outcomes and measuresThe prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.ResultsAmong 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF.Conclusions and relevanceIn this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.

Dataset Information

Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.

Publications

Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy.

Similar Datasets

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