.2017 Dec 7;101(6):1013-1020.

doi: 10.1016/j.ajhg.2017.11.004.

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

Sonja Martin¹, Adam Chamberlin², Deepali N Shinde², Maja Hempel³, Tim M Strom⁴, Allison Schreiber⁵, Jessika Johannsen⁶, Lilian Bomme Ousager⁷, Martin J Larsen⁷, Lars Kjaersgaard Hansen⁸, Ali Fatemi⁹, Julie S Cohen¹⁰, Johannes Lemke¹, Kristina P Sørensen⁷, Katherine L Helbig², Davor Lessel³, Rami Abou Jamra¹¹

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: rami.aboujamra@medizin.uni-leipzig.de.

PMID:29220673
PMCID: PMC5812909
DOI: 10.1016/j.ajhg.2017.11.004

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

Sonja Martin et al. Am J Hum Genet.2017.

.2017 Dec 7;101(6):1013-1020.

doi: 10.1016/j.ajhg.2017.11.004.

Authors

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: rami.aboujamra@medizin.uni-leipzig.de.

PMID:29220673
PMCID: PMC5812909
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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Figures

**Figure 1**
Structure of GRIA4 and Variant Location In addition, we show the allele count of genetic variants reported by gnomAD for the canonical transcript ENST00000282499 (GenBank:NM_000829.3). At position Arg697, where we describe the variant p.Arg697Pro in proband 5 in this report, another variant (p.Arg697Gln) is reported in gnomAD. In the main text, we describe the most likely mild impact of this change on the function of the protein. The figure was made with the help of Protter.

**Figure 2**
Tetrameric Structure of GRIA4 with Variants and Allosteric Movements The structure of GRIA4 was built off the homologous structure of GRIA2 forRattus norvegicus in the complex with an agonist (PDB:3KG2⁴⁵). The homology model of Gria4 was built off the homology modeling module of ROSETTA, where the sequence alignments were generated with TCOFFEE., The energy calculations of both and the destabilization of internal structure were calculated with the FoldX program. The images were generated with PyMOL (PyMOL Molecular Graphics System, v.1.8, Schrödinger). (A) GRIA4 tetramer with residues in the SYTANLAAF motif of M3. The residue positions of missense variants are indicated by red sticks. (B) GRIA4 tetramer with a variant in the ligand binding domain. The residue position of wild-type Arg697 is indicated by red sticks. (C) Arg697 moves by more than 10 Å from the ligand-bound (green; PDB:3KG2¹⁰) to theapo (yellow; PDB:4U2P⁶²) state. Arg697 interacts with residues on the adjacent monomer (gray), including the repulsive Lys787 and Lys792 (red sticks) in the ligand-bound state and the attractive Glu444 (blue sticks) in theapo state.

See this image and copyright information in PMC

References

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

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

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