2. Academic Validation
  3. De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities

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

  • Am J Hum Genet. 2017 Dec 7;101(6):1013-1020. doi: 10.1016/j.ajhg.2017.11.004.
Sonja Martin 1,  Adam Chamberlin 2,  Deepali N Shinde 2,  Maja Hempel 3,  Tim M Strom 4,  Allison Schreiber 5,  Jessika Johannsen 6,  Lilian Bomme Ousager 7,  Martin J Larsen 7,  Lars Kjaersgaard Hansen 8,  Ali Fatemi 9,  Julie S Cohen 10,  Johannes Lemke 1,  Kristina P Sørensen 7,  Katherine L Helbig 2,  Davor Lessel 3,  Rami Abou Jamra 11
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
  • 2 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92565, USA.
  • 3 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 4 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 5 Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 6 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 7 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
  • 8 Department of Paediatrics, Odense University Hospital, 5000 Odense, Denmark.
  • 9 Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Departments of Neurology and Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
  • 10 Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
  • 11 Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany. Electronic address: [email protected].
PMID: 29220673 DOI: 10.1016/j.ajhg.2017.11.004
Abstract

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.

Keywords

AMPA receptor; GRIA4; GluR4; de novo; exome sequencing; intellectual disability; seizures; speech delay.

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