Bàrbara Torrico, Ester Antón-Galindo, Noèlia Fernàndez-Castillo, Eva Rojo-Francàs, Sadaf Ghorbani, Laura Pineda-Cirera, Amaia Hervás, Isabel Rueda, Estefanía Moreno, Janice M. Fullerton, Vicent Casadó, Jan K. Buitelaar, Nanda Rommelse, Barbara Franke, Andreas Reif, Andreas Geburtig-Chiocchetti, Christine M. Freitag, Rune Kleppe, Jan Haavik, Claudio Toma, Bru Cormand
- 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.
MetadatenAuthor: | Bàrbara Torrico, Ester Antón-GalindoORCiD, Noèlia Fernàndez-CastilloORCiDGND, Eva Rojo-FrancàsORCiD, Sadaf Ghorbani, Laura Pineda-CireraORCiD, Amaia HervásORCiD, Isabel Rueda, Estefanía MorenoORCiD, Janice M. FullertonORCiD, Vicent Casadó, Jan K. BuitelaarORCiDGND, Nanda Rommelse, Barbara FrankeORCiDGND, Andreas ReifORCiDGND, Andreas Geburtig-ChiocchettiORCiDGND, Christine M. FreitagORCiDGND, Rune KleppeORCiD, Jan HaavikORCiD, Claudio TomaORCiD, Bru CormandORCiD |
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URN: | urn:nbn:de:hebis:30:3-554315 |
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DOI: | https://doi.org/10.3390/jcm9061851 |
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ISSN: | 2077-0383 |
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Parent Title (English): | Journal of Clinical Medicine |
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Publisher: | MDPI |
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Place of publication: | Basel |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2020/06/13 |
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Date of first Publication: | 2020/06/13 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/08/28 |
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Tag: | 14-3-3 gene family; YWHAE; YWHAZ; autism; common variants; rare variants; schizophrenia; transcriptomics |
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Volume: | 9 |
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Issue: | 1851 |
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Page Number: | 21 |
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HeBIS-PPN: | 469758422 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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