Abstract
GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.
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Acknowledgements
The authors thank Ms. Kaori Takabe, Mr. Takabumi Miyama, Ms. Nobuko Watanabe, Ms. Mai Sato, and Ms. Sayaka Sugimoto at Department of Human Genetics, Yokohama City University Graduate School of Medicine, and S. Kondo at Tokyo University of Science for their technical assistance, and the Drosophila Genetic Resource Center, Kyoto Institute of Technology, for providing the fly strains. They are also grateful to Edanz (https://jp.edanz.com/ac) for editing the English text of a draft of this manuscript. This work was supported by Japan Agency for Medical Research and Development (AMED) [JP20ek0109486, JP21ek0109549, JP21cm0106503, and JP21ek0109493 to N.M.; and JP19ek0109288 to K. Saito]; Japan Society for the Promotion of Science (JSPS) KAKENHI [JP20K16932 to K. Hamanaka, JP 20K17428 to N.T., JP 21k15097 to Y.U., JP20K17936 to A.F., and JP20K07907 to S.M.]; and an intramural Grant of Yokohama City University (to K. Hamanaka).
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439_2021_2416_MOESM1_ESM.png
Fig. S1 Structural considerations of Gly630Arg variation in GluA3 (a) Close-up views of the region around Gly598 in mouse GluA2 (Gly630 in human GluA3) in the structures calculated by FoldX. The main chain Cα atom of Gly598 and the side chain of Ala583 are shown as spheres, and the side chains of the residues predicted to clash with the variant Arg598 are indicated by transparent spheres. (b) The free energy changes due to the variation of p.Gly598Arg in mouse GluA2 (p.Gly630Arg in human GluA3) are shown as in Figure 2d. (PNG 9539 kb)
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Hamanaka, K., Miyoshi, K., Sun, JH. et al. Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. Hum Genet 141, 283–293 (2022). https://doi.org/10.1007/s00439-021-02416-7
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DOI: https://doi.org/10.1007/s00439-021-02416-7