A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.
A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.
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DOI：
10.1038/s41598-018-33924-8
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发表时间：
2018-10-19
影响因子：
4.6
通讯作者：
Gennarelli M
中科院分区：
文献类型：
--
作者：
Magri C;Giacopuzzi E;La Via L;Bonini D;Ravasio V;Elhussiny MEA;Orizio F;Gangemi F;Valsecchi P;Bresciani R;Barbon A;Vita A;Gennarelli M
最近，通过对精神分裂症（SCZ）患者的全外显子组测序，我们鉴定了一个谷氨酸脱羧酶1（GAD 1）基因中新型错义取代（c.391 A > G）的纯合受试者。GAD 1编码GAD 67酶，催化L-谷氨酸产生γ-氨基丁酸（GABA）。在这里，我们研究了这种突变对GAD 67活性，二聚化和亚细胞定位的影响。生物化学测定显示，c.391 A > G使GAD 67酶活性降低约30%，这可能是由于纯合突变体的同二聚化受损，如邻位连接测定所强调的。4，225例SCZ患者和5，834例对照者中“GABA能系统”120个基因的突变筛查（dbGaP：phs000473.v1.p2），没有鉴定出GAD 1中超罕见变异纯合的其他病例，但强调了GABA系统基因中罕见变异纯合病例的频率增加（SCZ：0.14% vs.对照：0.00%; p值= 0.0055）。总之，本研究证明了c.391 A > G变体的功能影响及其生物学效应使其成为SCZ风险变体的良好候选者。这项研究也支持GABA能基因的超罕见变异参与SCZ的发病机制。
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.
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影响因子：
4.4
作者：
Battaglioli, G;Liu, HC;Martin, DL
通讯作者：
Martin, DL
影响因子：
4.5
作者：
Keller MC;Simonson MA;Ripke S;Neale BM;Gejman PV;Howrigan DP;Lee SH;Lencz T;Levinson DF;Sullivan PF;Schizophrenia Psychiatric Genome-Wide Association Study Consortium
通讯作者：
Schizophrenia Psychiatric Genome-Wide Association Study Consortium
影响因子：
3.7
作者：
Giacopuzzi E;Gennarelli M;Minelli A;Gardella R;Valsecchi P;Traversa M;Bonvicini C;Vita A;Sacchetti E;Magri C
通讯作者：
Magri C
影响因子：
5.3
作者：
Huang, Hsien-Sung;Matevossian, Anouch;Akbarian, Schahram
通讯作者：
Akbarian, Schahram
影响因子：
3.7
作者：
Huang, Hsien-Sung;Akbarian, Schahram
通讯作者：
Akbarian, Schahram