Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

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J Psychiatry Neurosci 2018;43(4):223-244

Jordi Soler, MSc; Lourdes Fañanás, MD, PhD; Mara Parellada, MD, PhD; Marie-Odile Krebs, MD, PhD; Guy A. Rouleau, MD, PhD; Mar Fatjó-Vilas, PhD

Scaffolding proteins represent an evolutionary solution to controlling the specificity of information transfer in intracellular networks. They are highly concentrated in complexes located in specific subcellular locations. One of these complexes is the postsynaptic density of the excitatory synapses. There, scaffolding proteins regulate various processes related to synaptic plasticity, such as glutamate receptor trafficking and signalling, and dendritic structure and function. Most scaffolding proteins can be grouped into 4 main families: discs large (DLG), discs-large-associated protein (DLGAP), Shank and Homer. Owing to the importance of scaffolding proteins in postsynaptic density architecture, it is not surprising that variants in the genes that code for these proteins have been associated with neuropsychiatric diagnoses, including schizophrenia and autism-spectrum disorders. Such evidence, together with the clinical, neurobiological and genetic overlap described between schizophrenia and autism-spectrum disorders, suggest that alteration of scaffolding protein dynamics could be part of the pathophysiology of both. However, despite the potential importance of scaffolding proteins in these psychiatric conditions, no systematic review has integrated the genetic and molecular data from studies conducted in the last decade. This review has the following goals: to systematically analyze the literature in which common and/or rare genetic variants (single nucleotide polymorphisms, single nucleotide variants and copy number variants) in the scaffolding family genes are associated with the risk for either schizophrenia or autism-spectrum disorders; to explore the implications of the reported genetic variants for gene expression and/or protein function; and to discuss the relationship of these genetic variants to the shared genetic, clinical and cognitive traits of schizophrenia and autism-spectrum disorders.


Submitted Apr. 5, 2017; Revised Oct. 18, 2017; Accepted Nov. 13, 2017; Published online first May 29, 2018

Acknowledgements: This study was supported by: the Network of European Funding for Neuroscience Research, ERA-NET NEURON (PiM2010ERN-00642); Instituto de Salud Carlos III through the project PI15/01420 (co-funded by European Regional Development Fund /European Social Fund, “Investing in your future”); and SAF 2015-71526-REDT; and Ajuts de Personal Investigador predoctoral en Formació (APIF) to J Soler, 2017-2018. Thanks to the Comissionat per a Universitats i Recerca del DIUE (2014SGR1636).

Affiliations: From the Secció Zoologia i Antropologia Biològica, Dept Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain (Soler, Fañanás, Fatjó-Vilas); the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Soler, Fañanás, Parellada, Fatjó-Vilas); Servicio de Psiquiatría del Niño y del Adolescente, Hospital General Universitario Gregorio Marañón, Madrid, Spain, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón (IiSGM), Departamento de Psiquiatría, Facultad de Medicina, Universidad Complutense, Madrid, Spain (Parellada); the Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Faculté de Médecine Paris Descartes, Paris, France (Krebs); the Université Paris Descartes, Inserm Centre de Psychiatrie et Neurosciences, Laboratoire de Physiopathologie des Maladies Psychiatriques, Paris, France (Krebs); the CNRS, GDR 3557, Institut de Psychiatrie, Paris, France (Krebs); the Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC (Rouleau); and the FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain (Fatjó-Vilas).

Competing interests: M. Parellada reports personal fees from Fundación Orange, outside the submitted work. M.-O. Krebs reports personal fees or travel grant from Janssen and Otsuka-Lundbeck, outside the submitted work. No other competing interests declared.

Contributors: J. Soler and M. Fatjó-Vilas designed the study and acquired the data, which all authors analzyed. J. Soler and M. FatjóVilas wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170066

Correspondence to: M. Fatjó-Vilas, Secció Zoologia i Antropologia Biològica, Dept Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain; mar.fatjovilas@ub.edu