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Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect

Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an “involution” phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small...

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Autores principales: Grigorenko, Anastasia P., Protasova, Maria S., Lisenkova, Alexandra A., Reshetov, Denis A., Andreeva, Tatiana V., Garcias, Gilberto De Lima, Martino Roth, Maria Da Graça, Papassotiropoulos, Andreas, Rogaev, Evgeny I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834146/
https://www.ncbi.nlm.nih.gov/pubmed/35159210
http://dx.doi.org/10.3390/cells11030400
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author Grigorenko, Anastasia P.
Protasova, Maria S.
Lisenkova, Alexandra A.
Reshetov, Denis A.
Andreeva, Tatiana V.
Garcias, Gilberto De Lima
Martino Roth, Maria Da Graça
Papassotiropoulos, Andreas
Rogaev, Evgeny I.
author_facet Grigorenko, Anastasia P.
Protasova, Maria S.
Lisenkova, Alexandra A.
Reshetov, Denis A.
Andreeva, Tatiana V.
Garcias, Gilberto De Lima
Martino Roth, Maria Da Graça
Papassotiropoulos, Andreas
Rogaev, Evgeny I.
author_sort Grigorenko, Anastasia P.
collection PubMed
description Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an “involution” phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 (GRID2) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA.
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spelling pubmed-88341462022-02-12 Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect Grigorenko, Anastasia P. Protasova, Maria S. Lisenkova, Alexandra A. Reshetov, Denis A. Andreeva, Tatiana V. Garcias, Gilberto De Lima Martino Roth, Maria Da Graça Papassotiropoulos, Andreas Rogaev, Evgeny I. Cells Article Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an “involution” phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 (GRID2) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA. MDPI 2022-01-25 /pmc/articles/PMC8834146/ /pubmed/35159210 http://dx.doi.org/10.3390/cells11030400 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grigorenko, Anastasia P.
Protasova, Maria S.
Lisenkova, Alexandra A.
Reshetov, Denis A.
Andreeva, Tatiana V.
Garcias, Gilberto De Lima
Martino Roth, Maria Da Graça
Papassotiropoulos, Andreas
Rogaev, Evgeny I.
Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title_full Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title_fullStr Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title_full_unstemmed Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title_short Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect
title_sort neurodevelopmental syndrome with intellectual disability, speech impairment, and quadrupedia is associated with glutamate receptor delta 2 gene defect
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834146/
https://www.ncbi.nlm.nih.gov/pubmed/35159210
http://dx.doi.org/10.3390/cells11030400
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