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Article

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

1
Center for Genetics and Life Science, Sirius University of Science and Technology, 354340 Sochi, Russia
2
Laboratory of Evolutionary Genomics, Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia
3
Department of Psychiatry, UMass Chan Medical School, Shrewsbury, MA 01545, USA
4
Center for Genetics and Genetic Technologies, Department of Genetics, Faculty of Biology, Lomonosov Moscow State University, 119192 Moscow, Russia
5
Catholic University of Pelotas, Pelotas 96015-560, RS, Brazil
6
Federal University of Pelotas, Pelotas 96010-610, RS, Brazil
7
Transfaculty Research Platform, University of Basel, CH-4055 Basel, Switzerland
8
Psychiatric University Clinics, University of Basel, CH-4055 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Authors contributed equally to this manuscript.
Academic Editors: Illana Gozes and Carmen Laura Sayas
Cells 2022, 11(3), 400; https://doi.org/10.3390/cells11030400
Received: 7 December 2021 / Revised: 16 January 2022 / Accepted: 19 January 2022 / Published: 25 January 2022
(This article belongs to the Special Issue Mechanisms of Neurodevelopment and Neurodegeneration)
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. View Full-Text
Keywords: disequilibrium syndrome; quadrupedal locomotion; speech; congenital cerebellar ataxia; mental retardation; intellectual disability; cerebellum hypoplasia disequilibrium syndrome; quadrupedal locomotion; speech; congenital cerebellar ataxia; mental retardation; intellectual disability; cerebellum hypoplasia
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MDPI and ACS Style

Grigorenko, A.P.; Protasova, M.S.; Lisenkova, A.A.; Reshetov, D.A.; Andreeva, T.V.; Garcias, G.D.L.; Martino Roth, M.D.G.; Papassotiropoulos, A.; Rogaev, E.I. Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect. Cells 2022, 11, 400. https://doi.org/10.3390/cells11030400

AMA Style

Grigorenko AP, Protasova MS, Lisenkova AA, Reshetov DA, Andreeva TV, Garcias GDL, Martino Roth MDG, Papassotiropoulos A, Rogaev EI. Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect. Cells. 2022; 11(3):400. https://doi.org/10.3390/cells11030400

Chicago/Turabian Style

Grigorenko, Anastasia P., Maria S. Protasova, Alexandra A. Lisenkova, Denis A. Reshetov, Tatiana V. Andreeva, Gilberto D.L. Garcias, Maria D.G. Martino Roth, Andreas Papassotiropoulos, and Evgeny I. Rogaev. 2022. "Neurodevelopmental Syndrome with Intellectual Disability, Speech Impairment, and Quadrupedia Is Associated with Glutamate Receptor Delta 2 Gene Defect" Cells 11, no. 3: 400. https://doi.org/10.3390/cells11030400

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