Endele, Sabine ; Rosenberger, Georg ; Geider, Kirsten ; Popp, Bernt ; Tamer, Ceyhun ; Stefanova, Irina ; Milh, Mathieu ; Kortüm, Fanny ; Fritsch, Angela ; Pientka, Friederike K. ; Hellenbroich, Yorck ; Kalscheuer, Vera M. ; Kohlhase, Jürgen ; Moog, Ute ; Rappold, Gudrun ; Rauch, Anita ; Ropers, Hans-Hilger ; Spiczak, Sarah von ; Tönnies, Holger ; Villeneuve, Nathalie ; Villard, Laurent ; Zabel, Bernhard ; Zenker, Martin ; Laube, Bodo ; Reis, André ; Wieczorek, Dagmar ; Maldergem, Lionel van ; Kutsche, Kerstin (2010)
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
In: Nature genetics, 42 (11)
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2010 |
| Autor(en): | Endele, Sabine ; Rosenberger, Georg ; Geider, Kirsten ; Popp, Bernt ; Tamer, Ceyhun ; Stefanova, Irina ; Milh, Mathieu ; Kortüm, Fanny ; Fritsch, Angela ; Pientka, Friederike K. ; Hellenbroich, Yorck ; Kalscheuer, Vera M. ; Kohlhase, Jürgen ; Moog, Ute ; Rappold, Gudrun ; Rauch, Anita ; Ropers, Hans-Hilger ; Spiczak, Sarah von ; Tönnies, Holger ; Villeneuve, Nathalie ; Villard, Laurent ; Zabel, Bernhard ; Zenker, Martin ; Laube, Bodo ; Reis, André ; Wieczorek, Dagmar ; Maldergem, Lionel van ; Kutsche, Kerstin |
| Art des Eintrags: | Bibliographie |
| Titel: | Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes |
| Sprache: | Englisch |
| Publikationsjahr: | 2010 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Nature genetics |
| Jahrgang/Volume einer Zeitschrift: | 42 |
| (Heft-)Nummer: | 11 |
| Kurzbeschreibung (Abstract): | N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Neurophysiologie und neurosensorische Systeme ?? fb10_zoologie ?? |
| Hinterlegungsdatum: | 11 Apr 2011 09:11 |
| Letzte Änderung: | 30 Jul 2021 06:43 |
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