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Rare CACNA1H and RELN variants interact through mTORC1 pathway in oligogenic autism spectrum disorder.
Teles E Silva, André Luíz; Glaser, Talita; Griesi-Oliveira, Karina; Corrêa-Velloso, Juliana; Wang, Jaqueline Yu Ting; da Silva Campos, Gabriele; Ulrich, Henning; Balan, Andrea; Zarrei, Mehdi; Higginbotham, Edward J; Scherer, Stephen W; Passos-Bueno, Maria Rita; Sertié, Andrea Laurato.
Afiliação
  • Teles E Silva AL; Hospital Israelita Albert Einstein, São Paulo, Brazil.
  • Glaser T; Centro de Estudos do Genoma Humano e Células Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
  • Griesi-Oliveira K; Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
  • Corrêa-Velloso J; Hospital Israelita Albert Einstein, São Paulo, Brazil.
  • Wang JYT; Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
  • da Silva Campos G; Centro de Estudos do Genoma Humano e Células Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
  • Ulrich H; Centro de Estudos do Genoma Humano e Células Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
  • Balan A; Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
  • Zarrei M; Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
  • Higginbotham EJ; The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Scherer SW; The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Passos-Bueno MR; The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Sertié AL; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Transl Psychiatry ; 12(1): 234, 2022 06 06.
Article em En | MEDLINE | ID: mdl-35668055
Oligogenic inheritance of autism spectrum disorder (ASD) has been supported by several studies. However, little is known about how the risk variants interact and converge on causative neurobiological pathways. We identified in an ASD proband deleterious compound heterozygous missense variants in the Reelin (RELN) gene, and a de novo splicing variant in the Cav3.2 calcium channel (CACNA1H) gene. Here, by using iPSC-derived neural progenitor cells (NPCs) and a heterologous expression system, we show that the variant in Cav3.2 leads to increased calcium influx into cells, which overactivates mTORC1 pathway and, consequently, further exacerbates the impairment of Reelin signaling. Also, we show that Cav3.2/mTORC1 overactivation induces proliferation of NPCs and that both mutant Cav3.2 and Reelin cause abnormal migration of these cells. Finally, analysis of the sequencing data from two ASD cohorts-a Brazilian cohort of 861 samples, 291 with ASD; the MSSNG cohort of 11,181 samples, 5,102 with ASD-revealed that the co-occurrence of risk variants in both alleles of Reelin pathway genes and in one allele of calcium channel genes confer significant liability for ASD. Our results support the notion that genes with co-occurring deleterious variants tend to have interconnected pathways underlying oligogenic forms of ASD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canais de Cálcio Tipo T / Transtorno do Espectro Autista Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Transl Psychiatry Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Canais de Cálcio Tipo T / Transtorno do Espectro Autista Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Transl Psychiatry Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos