Cargando…
A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes
The metabotropic glutamate receptor 7 (mGlu(7)) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934925/ https://www.ncbi.nlm.nih.gov/pubmed/33476302 http://dx.doi.org/10.1172/jci.insight.143324 |
_version_ | 1783660911392718848 |
---|---|
author | Fisher, Nicole M. AlHashim, Aqeela Buch, Aditi B. Badivuku, Hana Samman, Manar M. Weiss, Kelly M. Cestero, Gabriela I. Does, Mark D. Rook, Jerri M. Lindsley, Craig W. Conn, P. Jeffrey Gogliotti, Rocco G. Niswender, Colleen M. |
author_facet | Fisher, Nicole M. AlHashim, Aqeela Buch, Aditi B. Badivuku, Hana Samman, Manar M. Weiss, Kelly M. Cestero, Gabriela I. Does, Mark D. Rook, Jerri M. Lindsley, Craig W. Conn, P. Jeffrey Gogliotti, Rocco G. Niswender, Colleen M. |
author_sort | Fisher, Nicole M. |
collection | PubMed |
description | The metabotropic glutamate receptor 7 (mGlu(7)) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu(7) ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu(7)-I154T mutant reveal that this substitution resulted in significant loss of mGlu(7) protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu(7)–global KO mice, mGlu(7)-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu(7) receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population. |
format | Online Article Text |
id | pubmed-7934925 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-79349252021-03-09 A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes Fisher, Nicole M. AlHashim, Aqeela Buch, Aditi B. Badivuku, Hana Samman, Manar M. Weiss, Kelly M. Cestero, Gabriela I. Does, Mark D. Rook, Jerri M. Lindsley, Craig W. Conn, P. Jeffrey Gogliotti, Rocco G. Niswender, Colleen M. JCI Insight Research Article The metabotropic glutamate receptor 7 (mGlu(7)) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu(7) ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu(7)-I154T mutant reveal that this substitution resulted in significant loss of mGlu(7) protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu(7)–global KO mice, mGlu(7)-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu(7) receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population. American Society for Clinical Investigation 2021-02-22 /pmc/articles/PMC7934925/ /pubmed/33476302 http://dx.doi.org/10.1172/jci.insight.143324 Text en © 2021 Fisher et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Fisher, Nicole M. AlHashim, Aqeela Buch, Aditi B. Badivuku, Hana Samman, Manar M. Weiss, Kelly M. Cestero, Gabriela I. Does, Mark D. Rook, Jerri M. Lindsley, Craig W. Conn, P. Jeffrey Gogliotti, Rocco G. Niswender, Colleen M. A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title | A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title_full | A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title_fullStr | A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title_full_unstemmed | A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title_short | A GRM7 mutation associated with developmental delay reduces mGlu(7) expression and produces neurological phenotypes |
title_sort | grm7 mutation associated with developmental delay reduces mglu(7) expression and produces neurological phenotypes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934925/ https://www.ncbi.nlm.nih.gov/pubmed/33476302 http://dx.doi.org/10.1172/jci.insight.143324 |
work_keys_str_mv | AT fishernicolem agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT alhashimaqeela agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT buchaditib agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT badivukuhana agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT sammanmanarm agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT weisskellym agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT cesterogabrielai agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT doesmarkd agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT rookjerrim agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT lindsleycraigw agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT connpjeffrey agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT gogliottiroccog agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT niswendercolleenm agrm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT fishernicolem grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT alhashimaqeela grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT buchaditib grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT badivukuhana grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT sammanmanarm grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT weisskellym grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT cesterogabrielai grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT doesmarkd grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT rookjerrim grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT lindsleycraigw grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT connpjeffrey grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT gogliottiroccog grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes AT niswendercolleenm grm7mutationassociatedwithdevelopmentaldelayreducesmglu7expressionandproducesneurologicalphenotypes |