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Open AccessArticle

Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

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Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
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Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
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Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, N5009 Bergen, Norway
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Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, 08221 Terrassa, Spain
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IGAIN, Global Institute of Integral Attention to Neurodevelopment, 08007 Barcelona, Spain
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Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
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Neuroscience Research Australia, Sydney, NSW 2031, Australia
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School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
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Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
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Karakter Child and Adolescent Psychiatry University Centre, 6525 GC Nijmegen, The Netherlands
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Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
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Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
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Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
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Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence Frankfurt, JW Goethe University, 60323 Frankfurt am Main, Germany
17
Division of Psychiatry, Haukeland University Hospital, 5021 Bergen, Norway
18
Centro de Biología Molecular “Severo Ochoa”, Universidad Autónoma de Madrid/CSIC, C/Nicolás Cabrera, 1, Campus UAM, 28049 Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors equally contributed to this work.
These authors equally supervised this work.
J. Clin. Med. 2020, 9(6), 1851; https://doi.org/10.3390/jcm9061851
Received: 30 April 2020 / Revised: 9 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue Genetics of Autism Spectrum Disorders)
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. View Full-Text
Keywords: autism; 14-3-3 gene family; rare variants; common variants; transcriptomics; schizophrenia; YWHAZ; YWHAE autism; 14-3-3 gene family; rare variants; common variants; transcriptomics; schizophrenia; YWHAZ; YWHAE
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Torrico, B.; Antón-Galindo, E.; Fernàndez-Castillo, N.; Rojo-Francàs, E.; Ghorbani, S.; Pineda-Cirera, L.; Hervás, A.; Rueda, I.; Moreno, E.; Fullerton, J.M.; Casadó, V.; Buitelaar, J.K.; Rommelse, N.; Franke, B.; Reif, A.; Chiocchetti, A.G.; Freitag, C.; Kleppe, R.; Haavik, J.; Toma, C.; Cormand, B. Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses. J. Clin. Med. 2020, 9, 1851.

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