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

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.

Unusual double mutation in MECP2 and CDKL5 genes in Rett-like syndrome: Correlation with phenotype and genes expression.

INTRODUCTION: Rett syndrome (RTT) is a neuro-developmental disorder affecting almost exclusively females and it divided into classical and atypical forms of the disease. RTT-like syndrome was also described and presents an overlapping phenotype of RTT. RTT-like syndrome has been associated with several genes including MECP2 and CDKL5 having common biological pathways and regulatory interactions especially during neural maturation and synaptogenesis. METHODS: We report patient with Rett-like syndrome for whom clinical features and their progression guided toward the screening of two candidate genes MECP2 and CDKL5 by sequencing. Severity score was evaluated by "Rett Assessment Rating Scale" (R.A.R.S.). Predictions of pahogenicity and functional effects used several bioinformatic tools and qRT-PCR was conducted to evaluate gene expression. RESULTS: Mutational screening revealed two mutations c.1065 C > A (p.S355R) in MECP2 gene and c.616 G > A (p.D206N) mutation in CDKL5 gene in the patient with a high R.A.R.S. Bioinformatic investigations predicted a moderate effect of p.S355R in MECP2 gene but a more pathogenic one of p.D206N mutation in CDKL5. Effect of c.616 G > A mutation on structure and stability of CDKL5 mRNA was confirmed by qRT-PCR. Additionally, analysis of gene expression revealed a drastic effect of CDKL5 mutant on its MeCP2 and Dnmt1 substrates and also on its MYCN regulator. CONCLUSIONS: The co-existence of the two mutations in CDKL5 and MECP2 genes could explain the severe phenotype in our patient with RTT-Like and is consistent with the data related to the interactions of CDKL5 with MeCP2 and Dnmt1 proteins.