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Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

ABSTRACT: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.

SUBMITTER: Lemke JR

PROVIDER: S-EPMC4898312 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

Lemke Johannes R JR Geider Kirsten K Helbig Katherine L KL Heyne Henrike O HO Schütz Hannah H Hentschel Julia J Courage Carolina C Depienne Christel C Nava Caroline C Heron Delphine D Møller Rikke S RS Hjalgrim Helle H Lal Dennis D Neubauer Bernd A BA Nürnberg Peter P Thiele Holger H Kurlemann Gerhard G Arnold Georgianne L GL Bhambhani Vikas V Bartholdi Deborah D Pedurupillay Christeen Ramane J CR Misceo Doriana D Frengen Eirik E Strømme Petter P Dlugos Dennis J DJ Doherty Emily S ES Bijlsma Emilia K EK Ruivenkamp Claudia A CA Hoffer Mariette J V MJ Goldstein Amy A Rajan Deepa S DS Narayanan Vinodh V Ramsey Keri K Belnap Newell N Schrauwen Isabelle I Richholt Ryan R Koeleman Bobby P C BP Sá Joaquim J Mendonça Carla C de Kovel Carolien G F CG Weckhuysen Sarah S Hardies Katia K De Jonghe Peter P De Meirleir Linda L Milh Mathieu M Badens Catherine C Lebrun Marine M Busa Tiffany T Francannet Christine C Piton Amélie A Riesch Erik E Biskup Saskia S Vogt Heinrich H Dorn Thomas T Helbig Ingo I Michaud Jacques L JL Laube Bodo B Syrbe Steffen S

Neurology 20160506 23

<h4>Objective</h4>To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.<h4>Methods</h4>We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.<h4>Results</h4>We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 ...[more]

PMID: 27164704

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Project description:Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.

Dataset Information

Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

Publications

Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

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