Danai Katsanevaki, Sally M. Till, Ingrid Buller-Peralta, Mohammad Sarfaraz Nawaz, Susana R. Louros, Vijayakumar Kapgal, Shashank Tiwari, Darren Walsh, Natasha J. Anstey, Nina G. Petrović, Alison Cormack, Vanesa Salazar-Sanchez, Anjanette Harris, William Farnworth-Rowson, Andrew Sutherland, Thomas C. Watson, Siyan Dimitrov, Adam D. Jackson, Daisy Arkell, Suryanarayan Biswal, Peter C. Kind
{"title":"Key roles of C2/GAP domains in SYNGAP1-related pathophysiology","authors":"Danai Katsanevaki, Sally M. Till, Ingrid Buller-Peralta, Mohammad Sarfaraz Nawaz, Susana R. Louros, Vijayakumar Kapgal, Shashank Tiwari, Darren Walsh, Natasha J. Anstey, Nina G. Petrović, Alison Cormack, Vanesa Salazar-Sanchez, Anjanette Harris, William Farnworth-Rowson, Andrew Sutherland, Thomas C. Watson, Siyan Dimitrov, Adam D. Jackson, Daisy Arkell, Suryanarayan Biswal, Peter C. Kind","doi":"10.1016/j.celrep.2024.114733","DOIUrl":null,"url":null,"abstract":"<p>Mutations in <em>SYNGAP1</em> are a common genetic cause of intellectual disability (ID) and a risk factor for autism. <em>SYNGAP1</em> encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of <em>SYNGAP1</em> are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures—key phenotypes shared with <em>Syngap</em> heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114733","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures—key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy.
期刊介绍:
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership.
The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.