TY  - JOUR
A1  - Torrico, Bàrbara
A1  - Antón-Galindo, Ester
A1  - Fernàndez-Castillo, Noèlia
A1  - Rojo-Francàs, Eva
A1  - Ghorbani, Sadaf
A1  - Pineda-Cirera, Laura
A1  - Hervás, Amaia
A1  - Rueda, Isabel
A1  - Moreno, Estefanía
A1  - Fullerton, Janice M.
A1  - Casadó, Vicent
A1  - Buitelaar, Jan K.
A1  - Rommelse, Nanda
A1  - Franke, Barbara
A1  - Reif, Andreas
A1  - Geburtig-Chiocchetti, Andreas
A1  - Freitag, Christine M.
A1  - Kleppe, Rune
A1  - Haavik, Jan
A1  - Toma, Claudio
A1  - Cormand, Bru
T1  - Involvement of the 14-3-3 gene family in autism spectrum disorder and schizophrenia: genetics, transcriptomics and functional analyses
T2  - Journal of Clinical Medicine
N2  - The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
KW  - autism
KW  - 14-3-3 gene family
KW  - rare variants
KW  - common variants
KW  - transcriptomics
KW  - schizophrenia
KW  - YWHAZ
KW  - YWHAE
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55431
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-554315
SN  - 2077-0383
VL  - 9
IS  - 1851
PB  - MDPI
CY  - Basel
ER  -