| Autor: |
MAGRI, Chiara, GIACOPUZZI, Edoardo, BARBON, Alessandro, LA VIA, Luca, Mingardi, J, CONGIU, Chiara, ORIZIO, FLAVIA, BRESCIANI, Roberto, SACCHETTI, Emilio, GENNARELLI, Massimo |
| Přispěvatelé: |
Magri, C, Giacopuzzi, E, Barbon, A, LA VIA, L, Mingardi, J, Congiu, C, Orizio, F, Bresciani, R, Sacchetti, E, Gennarelli, M |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
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| Popis: |
An increased load of runs of homozygosity (ROHs) is considered a risk factor for schizophrenia (SZ), suggesting a potential role of recessive genotypes in the pathogenesis of SZ. The whole exome sequencing of SZ patients with high level of ROHs allowed us to identify some rare homozygous mutations with a high probability of being related to SZ, since mapping in neurodevelopment and GABA/glutamatergic synaptic transmission genes. Among these mutations, there was a novel missense substitution (c.391A>G; p.Thr131Ala) in the glutamate acid decarboxylase 1 (GAD1) gene (NM_000817) that encodes for the enzyme (GAD67) catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Since the GAD1 mRNA downregulation as well as reduced levels of GAD67 have been reported in post-mortem brains of SZ patients and since polymorphisms in the GAD1 promoter have been reported as risk factors for SZ, we assessed the biological effect of this mutation to corroborate its potential role in SZ. Confocal immunofluorescence analysis of transfected cells revealed that both the exogenous wild type (WT) and the mutated protein exhibit the same localization: mainly in the Golgi apparatus and in cytosolic vesicles. Biochemical assays showed that the amount of GABA produced by transfected cells expressing the mutated isoform was 30% lower than the amount produced by the cells expressing the WT isoform. These results corroborate the hypothesis that this mutation may impact on the SZ phenotype and supports the hypothesis that also rare recessive mutations are involved in the etiopathogenesis of SZ. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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