A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme

Chiara Magri, Edoardo Giacopuzzi, Luca La Via, Daniela Bonini, Viola Ravasio, Mohammed E.A. Elhussiny, Flavia Orizio, Fabrizio Gangemi, Paolo Valsecchi, Roberto Bresciani, Alessandro Barbon, Antonio Vita, Massimo Gennarelli

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Abstract

Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays. The mutational screening of 120 genes of the “GABAergic system” in a cohort of 4,225 SCZ cases and 5,834 controls (dbGaP: phs000473.v1.p2), did not identify other cases that were homozygous for ultra-rare variants in GAD1, but highlighted an increased frequency of cases that were homozygous for rare variants in genes of the GABA system (SCZ: 0.14% vs. Controls: 0.00%; p-value = 0.0055). In conclusion, this study demonstrates the functional impact of c.391 A > G variant and its biological effect makes it a good candidate as risk variant for SCZ. This study also supports an involvement of ultra-rare variants in GABAergic genes in the etiopathogenesis of SCZ.

Original languageEnglish
Article number15470
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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    Magri, C., Giacopuzzi, E., La Via, L., Bonini, D., Ravasio, V., Elhussiny, M. E. A., Orizio, F., Gangemi, F., Valsecchi, P., Bresciani, R., Barbon, A., Vita, A., & Gennarelli, M. (2018). A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme. Scientific Reports, 8(1), [15470]. https://doi.org/10.1038/s41598-018-33924-8