Key roles of C2/GAP domains in SYNGAP1-related pathophysiology
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.
Authors
- Sumantra Chattarji (ORCID: https://orcid.org/0000-0001-9962-3635)
- Shashank Tiwari (ORCID: https://orcid.org/0000-0002-2046-6946)
- Andrew Sutherland (ORCID: https://orcid.org/0000-0001-7907-5766)
- Alfredo Gonzalez‐Sulser (ORCID: https://orcid.org/0000-0003-3494-4029)
- Peter C. Kind (ORCID: https://orcid.org/0000-0002-4256-9639)
- Adam D. Jackson (ORCID: https://orcid.org/0000-0002-3554-6682)
- Michael A. Cousin (ORCID: https://orcid.org/0000-0002-1762-160X)
- Matthew W. Jones (ORCID: https://orcid.org/0000-0001-5396-3108)
- Oliver Hardt (ORCID: https://orcid.org/0000-0002-3975-9634)
- Nicholas Perentos (ORCID: https://orcid.org/0000-0001-9336-6180)
- Sally M. Till (ORCID: https://orcid.org/0000-0002-3114-9866)
- Kosala N. Dissanayake (ORCID: https://orcid.org/0009-0009-7105-8908)
- Sam A. Booker (ORCID: https://orcid.org/0000-0003-1980-9873)
- Anjanette Harris
- Daisy Arkell
- Thomas C. Watson (ORCID: https://orcid.org/0000-0002-5146-6981)
- Darren Walsh (ORCID: https://orcid.org/0000-0002-8010-8067)
- Danai Katsanevaki (ORCID: https://orcid.org/0000-0003-4395-6857)
- Susana R. Louros (ORCID: https://orcid.org/0000-0002-1012-0386)
- Emma R. Wood (ORCID: https://orcid.org/0000-0002-7508-9009)
- Ingrid Buller‐Peralta (ORCID: https://orcid.org/0000-0002-4427-9897)
- Natasha Anstey (ORCID: https://orcid.org/0000-0003-3530-009X)
- Lindsay Mizen (ORCID: https://orcid.org/0000-0002-3540-9717)
- Emily K. Osterweil (ORCID: https://orcid.org/0000-0003-0582-2284)
- David J. A. Wyllie (ORCID: https://orcid.org/0000-0002-4957-6049)
- Vijayakumar Kapgal
- Mohammad Nawaz (ORCID: https://orcid.org/0000-0003-4008-0976)
- Nina G Petrović
- Alison Cormack
- Vanesa Salazar-Sanchez
- William Farnworth-Rowson
- Suryanarayan Biswal
- Siyan Dimitrov
Institutions
- University of Nicosia (CY)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114733
- Citations
- 22
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 7.17
Funders
- Simons Foundation
- Wellcome Trust
- Medical Research Council