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

Anastasia P Grigorenko,Gilberto De Lima Garcias,Maria S Protasova,Alexandra A Lisenkova,Denis A Reshetov,Andreas Papassotiropoulos,Tatiana V Andreeva,Evgeny I Rogaev,Maria Da Graça Martino Roth

doi:10.3390/cells11030400

Abstract

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.

Highlights

A very rare case of cerebellar hypoplasia, quadrupedia or cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) or disequilibrium syndromes (DSs) is characterized by the lack of capacity for bipedal locomotion, ataxia, intellectual disability, and speech disturbance
Six genes with missense mutations which lead to a lack of bipedal locomotion have been previously described: VLDLR and RELN genes, both involved in neuronal migration in the developing brain [2,6]; the CA8 gene, which participates in the modulation of intracellular calcium signaling in the cerebellum [5]; the WDR81 (WD repeat domain 81) gene, which is highly expressed in Purkinje and photoreceptor cells and is involved in endolysosomal trafficking [7]; the ATP8A2 gene, which is responsible for the transport of aminophospholipids via the lipid flipping process [8]; and the TUBB2B gene, which encodes a beta isoform of tubulin—an essential component of the microtubule cytoskeleton [9]
We focused on patients from a Brazilian family, first described by Garcias and Roth, who possess distinctive features which were not specified in other cases of GRID2 gene pathology (SCAR18): quadrupedal locomotion, the absence of speech, severe intellectual disability, seizures, and some appearance features

Summary

Introduction

A very rare case of cerebellar hypoplasia, quadrupedia or cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) or disequilibrium syndromes (DSs) is characterized by the lack of capacity for bipedal locomotion, ataxia, intellectual disability, and speech disturbance. A similar phenotype was described in several consanguineous families in Turkey [1–4] and Iraq [5]. Despite similar clinical manifestations in all of the unrelated families described in the literature, this form of neurodevelopmental disorder is heterogeneous and is caused by mutations in different genes. We performed a comprehensive genetic analysis of a neurological case of quadrupedal locomotion with intellectual disability and the complete absence of speech, found in a Brazilian family [10]. We described the genetic cause of the disease in this family and analyzed the contribution of the GRID2 gene to bipedalism and speech development

Methods

Results

Discussion

Conclusion