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. 2013 Sep;45(9):1073-6.
doi: 10.1038/ng.2727. Epub 2013 Aug 11.

GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Gemma L Carvill  1 , Brigid M Regan, Simone C Yendle, Brian J O'Roak, Natalia Lozovaya, Nadine Bruneau, Nail Burnashev, Adiba Khan, Joseph Cook, Eileen Geraghty, Lynette G Sadleir, Samantha J Turner, Meng-Han Tsai, Richard Webster, Robert Ouvrier, John A Damiano, Samuel F Berkovic, Jay Shendure, Michael S Hildebrand, Pierre Szepetowski, Ingrid E Scheffer, Heather C Mefford
Affiliations

GRIN2A mutations cause epilepsy-aphasia spectrum disorders

Gemma L Carvill et al. Nat Genet. 2013 Sep.

Abstract

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.

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Figures

Figure 1
Figure 1
Phenotypes and segregation of GRIN2A mutations in four families with epilepsy-aphasia syndromes
Figure 2
Figure 2
NR2A-p.Thr531Met mutation increases mean open time of NMDA receptors. Left panels: representative steady-state unitary currents through (a) NR1/NR2A-wt and (b) NR1/NR2A-p.Thr531Met channels, recorded in cell-attached patches from transiently transfected COS-7 cells (n=5 to 7 cells). Holding potential +100 mV. Channels are activated by 50 μM glycine and 1 mM glutamate. o: open state; c: closed state; ms: milliseconds; pA: picoAmpere. Note that single channel amplitudes were not significantly affected by the mutation. Right panels: open duration histograms for the same single channel patches. The histograms were well fitted with single exponentials.
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