Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

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; Kosala N Dissanayake; Lindsay A M Mizen; Nikolas Perentos; Matt W Jones; Michael A Cousin; Sam A Booker; Emily K Osterweil; Sumantra Chattarji; David J A Wyllie; Alfredo Gonzalez-Sulser; Oliver Hardt; Emma R Wood; Peter C Kind

doi:10.1016/j.celrep.2024.114733

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

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 BiswalKosala N Dissanayake, Lindsay A M Mizen, Nikolas Perentos, Matt W Jones, Michael A Cousin, Sam A Booker, Emily K Osterweil, Sumantra Chattarji, David J A Wyllie, Alfredo Gonzalez-Sulser, Oliver Hardt, Emma R Wood, Peter C Kind^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Article number	114733
Journal	Cell Reports
Volume	43
Issue number	9
Early online date	11 Sept 2024
DOIs	https://doi.org/10.1016/j.celrep.2024.114733
Publication status	Published - 24 Sept 2024

Keywords / Materials (for Non-textual outputs)

epilepsy
SYNGAP1
exploration
rasopathy
learning and memory
CP: Neuroscience
neurodevelopmental disorder
synaptic plasticity
encephalopathy
autism
intellectual disability

Access to Document

10.1016/j.celrep.2024.114733Licence: Creative Commons: Attribution (CC-BY)

1-s2.0-S2211124724010842-mainFinal published version, 5.71 MBLicence: Creative Commons: Attribution (CC-BY)

MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD
Kind, P., Wood, E. & Wyllie, D.
MRC
1/09/16 → 28/02/21
Project: Research

Cite this

Katsanevaki, D., Till, S. M., Buller-Peralta, I., Nawaz, M. S., Louros, S. R., Kapgal, V., Tiwari, S., Walsh, D., Anstey, N. J., Petrović, N. G., Cormack, A., Salazar-Sanchez, V., Harris, A., Farnworth-Rowson, W., Sutherland, A., Watson, T. C., Dimitrov, S., Jackson, A. D., Arkell, D., ... Kind, P. C. (2024). Key roles of C2/GAP domains in SYNGAP1-related pathophysiology. Cell Reports, 43(9), Article 114733. https://doi.org/10.1016/j.celrep.2024.114733

@article{cff4d3ff44e74d7a8ed9e3308772576f,

title = "Key roles of C2/GAP domains in SYNGAP1-related pathophysiology",

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.",

keywords = "epilepsy, SYNGAP1, exploration, rasopathy, learning and memory, CP: Neuroscience, neurodevelopmental disorder, synaptic plasticity, encephalopathy, autism, intellectual disability",

author = "Danai Katsanevaki and Till, {Sally M} and Ingrid Buller-Peralta and Nawaz, {Mohammad Sarfaraz} and Louros, {Susana R} and Vijayakumar Kapgal and Shashank Tiwari and Darren Walsh and Anstey, {Natasha J} and Petrovi{\'c}, {Nina G} and Alison Cormack and Vanesa Salazar-Sanchez and Anjanette Harris and William Farnworth-Rowson and Andrew Sutherland and Watson, {Thomas C} and Siyan Dimitrov and Jackson, {Adam D} and Daisy Arkell and Suryanarayan Biswal and Dissanayake, {Kosala N} and Mizen, {Lindsay A M} and Nikolas Perentos and Jones, {Matt W} and Cousin, {Michael A} and Booker, {Sam A} and Osterweil, {Emily K} and Sumantra Chattarji and Wyllie, {David J A} and Alfredo Gonzalez-Sulser and Oliver Hardt and Wood, {Emma R} and Kind, {Peter C}",

year = "2024",

month = sep,

day = "24",

doi = "10.1016/j.celrep.2024.114733",

language = "English",

volume = "43",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "9",

}

Katsanevaki, D, Till, SM , Buller-Peralta, I , Nawaz, MS, Louros, SR, Kapgal, V , Tiwari, S , Walsh, D, Anstey, NJ, Petrović, NG, Cormack, A, Salazar-Sanchez, V, Harris, A, Farnworth-Rowson, W, Sutherland, A, Watson, TC, Dimitrov, S, Jackson, AD, Arkell, D, Biswal, S, Dissanayake, KN , Mizen, LAM, Perentos, N, Jones, MW, Cousin, MA , Booker, SA , Osterweil, EK, Chattarji, S, Wyllie, DJA , Gonzalez-Sulser, A , Hardt, O , Wood, ER & Kind, PC 2024, 'Key roles of C2/GAP domains in SYNGAP1-related pathophysiology', Cell Reports, vol. 43, no. 9, 114733. https://doi.org/10.1016/j.celrep.2024.114733

TY - JOUR

T1 - Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

AU - Katsanevaki, Danai

AU - Till, Sally M

AU - Buller-Peralta, Ingrid

AU - Nawaz, Mohammad Sarfaraz

AU - Louros, Susana R

AU - Kapgal, Vijayakumar

AU - Tiwari, Shashank

AU - Walsh, Darren

AU - Anstey, Natasha J

AU - Petrović, Nina G

AU - Cormack, Alison

AU - Salazar-Sanchez, Vanesa

AU - Harris, Anjanette

AU - Farnworth-Rowson, William

AU - Sutherland, Andrew

AU - Watson, Thomas C

AU - Dimitrov, Siyan

AU - Jackson, Adam D

AU - Arkell, Daisy

AU - Biswal, Suryanarayan

AU - Dissanayake, Kosala N

AU - Mizen, Lindsay A M

AU - Perentos, Nikolas

AU - Jones, Matt W

AU - Cousin, Michael A

AU - Booker, Sam A

AU - Osterweil, Emily K

AU - Chattarji, Sumantra

AU - Wyllie, David J A

AU - Gonzalez-Sulser, Alfredo

AU - Hardt, Oliver

AU - Wood, Emma R

AU - Kind, Peter C

PY - 2024/9/24

Y1 - 2024/9/24

N2 - 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.

AB - 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.

KW - epilepsy

KW - SYNGAP1

KW - exploration

KW - rasopathy

KW - learning and memory

KW - CP: Neuroscience

KW - neurodevelopmental disorder

KW - synaptic plasticity

KW - encephalopathy

KW - autism

KW - intellectual disability

U2 - 10.1016/j.celrep.2024.114733

DO - 10.1016/j.celrep.2024.114733

M3 - Article

C2 - 39269903

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 114733

ER -

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD

Cite this