Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation

Molecular Psychiatry, Год журнала: 2023, Номер 28(9), С. 3769 - 3781

Опубликована: Сен. 1, 2023

Abstract Microdeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized contribute 22q11.2DS pathogenesis; however, which six phenotypes their underlying mechanisms remain unresolved. To systematically test functional roles in neurodevelopment behavior, we generated mutants each 37 conserved zebrafish orthologs performed high throughput behavioral phenotyping using seven assays. Through this unbiased approach, identified five single-gene with partially overlapping phenotypes. Two these genes, mrpl40 prodha , encode proteins and, similar what observed mutants, pharmacologic inhibition during development results microcephaly. Single mutant analysis shows that both display aberrant neural stem progenitor cell proliferation, gene regulating distinct populations. Finally, double aggravated reveals previously unrecognized redundant role radial glia-like proliferation. Combined, our demonstrate critical populations developing vertebrate brain provide compelling evidence dysfunction linked volume models 22q11.2DS.

Язык: Английский

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Strategies for dissecting the complexity of neurodevelopmental disorders

Trends in Genetics, Год журнала: 2023, Номер 40(2), С. 187 - 202

Опубликована: Ноя. 8, 2023

Язык: Английский

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Convergent impact of schizophrenia risk genes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Март 30, 2022

ABSTRACT Genetic studies of schizophrenia reveal a complex polygenic risk architecture comprised hundreds variants; most are common in the population at-large, non-coding, and act by genetically regulating expression one or more gene targets (“eGenes”). It remains unclear how genetic variants predicted to confer individually small effects combine yield substantial clinical impacts aggregate. Here, we demonstrate that eGenes have shared downstream transcriptomic (“convergence”) may underlie unexpected interactions (“non-additive effects”) observed when manipulated combination. We apply pooled CRISPR approach perturb human induced pluripotent stem cell-derived glutamatergic neurons. The strength specificity convergence increased between functionally similar eGenes. Predicting might impact additive relationships loci inherited together, use an arrayed explore bidirectional combinatorial perturbations partially overlapping set fifteen When specifically considering groups synaptic epigenetic eGenes, eGene changes smaller than summing individual (“sub-additive effects”). Moreover, convergent non-additive overlap, suggesting functional redundancy be major mechanism underlying non-additivity. Combinatorial result outcomes not yet well-predicted single alone, indicating cannot necessarily extrapolated from experiments testing at time.

Язык: Английский

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Context-dependent hyperactivity in syngap1a and syngap1b zebrafish models of SYNGAP1-related disorder

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Июль 10, 2024

Background and aims SYNGAP1-related disorder (SYNGAP1-RD) is a prevalent genetic form of Autism Spectrum Disorder Intellectual Disability (ASD/ID) caused by de novo or inherited mutations in one copy the SYNGAP1 gene. In addition to ASD/ID, associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, gastrointestinal distress. Mechanistic links between these diverse variants remain obscure, therefore, our goal was generate zebrafish model which this range can be studied. Methods We used CRISPR/Cas9 introduce frameshift syngap1a syngap1b duplicates ( syngap1ab ) validated stable models for Syngap1 loss-of-function. Because extensively spliced, we mapped splice two b genes identified mammalian-like isoforms. then quantified locomotory behaviors larvae under three conditions that normally evoke different arousal states wild-type larvae: aversive, high-arousal acoustic, medium-arousal dark, low-arousal light stimuli. Results show indels produced loss-of-function alleles at RNA protein levels. Our analyses isoforms showed that, as mammals, N- C-termini are spliced. syngap1 α1-like variant maps exclusively Quantifying locomotor mutant hyperactive compared but differing degrees depending on stimulus. Hyperactivity most pronounced low settings, hyperactivity proportional number alleles. Limitations produce relatively subtle phenotypes mammals. For example, while mouse homozygotes die birth, syngap1ab−/− survive adulthood fertile, thus some aspects people SYNGAP1- Related not likely reflected zebrafish. Conclusion data support causal elevated especially environments.

Язык: Английский

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Review: Child Psychiatry in the Era of Genomics: The Promise of Translational Genetics Research for the Clinic

JAACAP Open, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

ObjectiveThere has been remarkable progress in recent years understanding the genetic underpinnings of child psychiatric disorders. Concurrently, testing is becoming increasingly available clinic. However, many clinicians report a lack familiarity with genetics and how might inform clinical evaluation. This review aims to introduce cutting-edge research discuss emerging role tests practice.MethodThis highlights major findings presented at Research Institute 69th American Academy Child Adolescent Psychiatry Annual Meeting.ResultsWe provide an overview critical concepts for discussion advances genetics, focusing on autism spectrum disorders, where whole exome sequencing led identification ∼250 high-confidence risk genes. We describe similar approaches gene discovery are beginning shed light architecture early-onset psychosis, Tourette's disorder, obsessive-compulsive other In addition, we practical limitations pharmacogenetic testing, ethical considerations, barriers testing. Finally, illustrate promise advancing our pathophysiology these disorders.ConclusionThis improve clinicians' knowledge evaluation management disorders potential groundbreaking field shape development new treatments.

Язык: Английский

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