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Molecular and cellular effects of a de novo mutation in the CACNA1H gene in autistic spectrum disorder

Grant number: 17/24833-2
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): May 01, 2018
Effective date (End): April 30, 2019
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Andréa Laurato Sertié
Grantee:André Luiz Teles e Silva
Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil


Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairment in reciprocal social communication, restricted repetitive and stereotyped patterns of behavior. Recent genomic studies have revealed that the genetic architecture of ASD is extremely complex and heterogeneous, and both rare and common genetic variants may contribute to its etiology. However, most of the known ASD risk genes carry rare de novo variants of high penetrance. Among these genes is CACNA1H, which encodes the ±1-subunit of the T-type low voltage dependent calcium (Ca2+) channel Cav3.2. The ±1 subunit forms the pore of the channel and controls the conductance and voltage-dependent kinetics of the channel. Influx of extracellular Ca2+ modulates several cellular processes, including neurotransmitter release, gene transcription, cell proliferation, migration, and the activity of intracellular signaling pathways, such as the PI3K-mTOR pathway. Loss-of-function missense variants in the CACNA1H gene have already been identified in patients with ASD, however, the mechanisms by which such mutations contribute to ASD have not yet been fully elucidated. Recently, we performed whole-exome sequencing in a subgroup of ASD patients - in whom we found PI3K-mTOR signaling hyperfunction - and identified in one patient (called as F2688) a de novo point mutation in the 5' splice donor site of intron 13 of the CACNA1H gene, which is predicted to alter mRNA, leading to the inclusion of 52 amino acid residues in the channel pore region. This project aims to verify whether the variant identified in the CACNA1H gene in patient F2688 is functional, i.e., leads to abnormal Ca2+ influx in patient-derived neural cells, and whether such alteration contributes to the dysfunctional PI3K-mTOR signaling pathway as well as to the abnormal migration observed in neural cells from this patient. In order to achieve this, we intend to use as an experimental model induced pluripotent stem cells-derived neuroprogenitor cells from patient F2688 and from control individuals, and we will perform analysis of CACNA1H gene and protein expression, calcium influx, electrophysiology, PI3K-mTOR pathway activity and cell migration. In addition, we intend to use a heterologous expression system to confirm the results. To date, there are no published studies on the relationship among Ca2+ channel dysfunction, PI3K-mTOR pathway and ASD, and the confirmation that the identified CACNA1H variant is functional will highlight the significance of Ca2+ channel dysfunction in ASD. (AU)

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