De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities

TY - JOUR

T1 - De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities

AU - Martin, Sonja

AU - Chamberlin, Adam

AU - Shinde, Deepali N

AU - Hempel, Maja

AU - Strom, Tim M

AU - Schreiber, Allison

AU - Johannsen, Jessika

AU - Ousager, Lilian Bomme

AU - Larsen, Martin J

AU - Hansen, Lars Kjaersgaard

AU - Fatemi, Ali

AU - Cohen, Julie S

AU - Lemke, Johannes

AU - Sørensen, Kristina P

AU - Helbig, Katherine L

AU - Lessel, Davor

AU - Abou Jamra, Rami

N1 - Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2017/12/7

Y1 - 2017/12/7

N2 - Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.

AB - Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.

KW - Journal Article

U2 - 10.1016/j.ajhg.2017.11.004

DO - 10.1016/j.ajhg.2017.11.004

M3 - SCORING: Journal article

C2 - 29220673

VL - 101

SP - 1013

EP - 1020

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 6

ER -