Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses.
Por:
Torrico B, Antón-Galindo E, Fernandez-Castillo N, Rojo-Francàs E, Ghorbani S, Pineda L, Hervás A, Rueda I, Moreno E, Fullerton JM, Casadó V, Buitelaar JK, Rommelse N, Franke B, Reif A, Chiocchetti AG, Freitag C, Kleppe R, Haavik J, Toma C and Cormand B
Publicada:
13 jun 2020
Ahead of Print:
13 jun 2020
Categoría:
Medicine (miscellaneous)
Resumen:
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3?) 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 14-3-3? 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 14-3-3? 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.
Filiaciones:
Torrico B:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Antón-Galindo E:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Fernandez-Castillo N:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Rojo-Francàs E:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Ghorbani S:
Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, N5009 Bergen, Norway
Pineda L:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Hervás A:
Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, 08221 Terrassa, Spain
IGAIN, Global Institute of Integral Attention to Neurodevelopment, 08007 Barcelona, Spain
Rueda I:
Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, 08221 Terrassa, Spain
Moreno E:
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Fullerton JM:
Neuroscience Research Australia, Sydney, NSW 2031, Australia
School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Casadó V:
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Buitelaar JK:
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
Karakter Child and Adolescent Psychiatry University Centre, 6525 GC Nijmegen, The Netherlands
Rommelse N:
Karakter Child and Adolescent Psychiatry University Centre, 6525 GC Nijmegen, The Netherlands
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
Franke B:
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 HR Nijmegen, The Netherlands
Reif A:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Chiocchetti AG:
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
Freitag C:
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
Kleppe R:
Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, N5009 Bergen, Norway
Division of Psychiatry, Haukeland University Hospital, 5021 Bergen, Norway
Haavik J:
Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, N5009 Bergen, Norway
Toma C:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Neuroscience Research Australia, Sydney, NSW 2031, Australia
School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid/CSIC, C/Nicolás Cabrera, 1, Campus UAM, 28049 Madrid, Spain
Cormand B:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Prevosti Building, floor 2, Av. Diagonal 643, 08028 Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), 08950 Esplugues de Llobregat, Spain
Green Published, gold
|