A large consanguineous family with a homozygous Metabotropic Glutamate Receptor 7 (mGlu7) variant and developmental epileptic encephalopathy: Effect on protein structure and ligand affinity

Abstract

Background: Developmental and epileptic encephalopathies (DEE) are chronic neurological conditions where epileptic activity contributes to the progressive disruption of brain function, frequently leading to impaired motor, cognitive and sensory development.

Patients and methods: The present study reports a clinical investigation and a molecular analysis by Next Generation Sequencing (NGS) of a large consanguineous family comprising several cases of developmental and epileptic encephalopathy. Bioinformatic prediction and molecular docking analysis were also carried out.

Results: The majority of patients in our studied family had severe developmental impairments, early-onset seizures, brain malformations such as cortical atrophy and microcephaly, developmental delays and intellectual disabilities. The molecular investigations revealed a novel homozygous variant c.1411G>A (p.Gly471Arg) in the GRM7 gene which was segregating with the disease in the family. Bioinformatic tools predicted its pathogenicity and docking analysis revealed its potential effects on mGlu7 protein binding to its ligand.

Conclusion: Our results contribute to a better understanding of the impact of GRM7 variants for the newly described associated phenotype.

Keywords: Developmental epileptic encephalopathy; GRM7 gene; Next generation sequencing.

Fig. 1

Pedigree of the large studied family with EE presenting the segregation of the GRM7 variant. Asterisk indicates the patient with West Syndrome whose DNA sample was sequenced using the TruSight One Sequencing Panel. Black shapes mark affected individuals. Gray shapes indicate those have not released medical records but the family informed us that they have a neurological disorder

Fig. 2

a Sleep (EEG) showing an aspect of hypsarrhythmia: high amplitude and irregular waves and spikes in a background of chaotic and disorganized activity. b Awake EEG showing multifocal spikes discharges. c, d Coronal section of brain MRI from patients carrying the p.Gly471Arg mGlu7 variant. c Coronal section of brain MRI of VI4 patient at the age of 10 years showed a cortical and sub-cortical atrophy. d Coronal section of brain MRI of VI1 patient at the age of 2 years showed a discrete hyper T2 of posterior SB

Fig. 3

Photographs showing dysmorphic features of affected family members: VI4 (a), VI8 (b), V1 (c) and VI6 (d). (Photographs reproduced with patients’ permission)

Fig. 4

a–a′ Prediction of the functional effect of p.Gly471Arg variant by Mutation Taster. b–b′ Differences in hydrogen bond connections between wild-type and mutated models: Gly471 establishes three hydrogen bonds with Arg197 and Asn468 (b), the Arg471 variant leads to an addition of two new hydrogen bonds with Leu186 and Tyr192 (b′). The wild type amino acids are colored in pink, the variant amino acid is colored in green. c–c′ Glutamate (Glu) recognition by mGlu7 protein. Hydrogen atoms attached at the C_α atom of the ligand (Glu) are modeled with the corresponding ideal geometries. Dark green and light grey lines indicate hydrogen-bonding while light green lines indicate VDW contact. d–d′ The ligand-binding pocket. The orientation of Glutamate docked into the putative active site of mGlu7. d The structure of wild-type mGlu7. (d′) The structure of the Gly471Arg mutant