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Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

Molecular Psychiatry volume 14, pages 705–718 (2009)Cite this article

Abstract

Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and βII isoenzymes result from the alternative splicing of the PKCβ gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P<0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P<0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P<0.01 and <0.05, respectively) according to qPCR. Protein amounts measured for the PKCβII isoform were similarly decreased by 35% (P=0.05). Decreased gene expression characterized patients carrying the ‘normal’ PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKCβ-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCβ roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKCβ roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.

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Acknowledgements

We gratefully acknowledge Laura Gaita and Rosanna D'Oronzio for technical assistance, Francis Rousseau and Anne Philippi (IntegraGen SA, Evry, France) for the genotyping and the population stratification analysis, Carlo Lenti and Roberto Rigardetto for contributing to patient recruitment, all the patients and families who generously contributed to these studies, and the Autism Tissue Program, Harvard Brain Tissue Resource Center, and Maryland NICHD Brain Tissue Center for providing the brain tissue samples. This work was supported by the Italian Ministry for University, Scientific Research and Technology (Programmi di Ricerca di Interesse Nazionale, prot. no.2006058195), the National Alliance for Autism Research (Princeton, NJ), the Cure Autism Now Foundation (Los Angeles, CA) and the Fondation Jerome Lejeune (Paris, France) to AMP, and by VUKC Startup Fund, R01 MH079299, and K02 MH070786 to KM.

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Author notes

  1. C Lintas and R Sacco: These authors contributed equally to this study.

Authors and Affiliations

  1. Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy

    C Lintas, R Sacco & A M Persico

  2. Department of Experimental Neurosciences, Laboratory of Molecular Psychiatry and Psychiatric Genetics, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy

    C Lintas, R Sacco & A M Persico

  3. Department of Psychiatry, Vanderbilt University, Nashville, TN, USA

    K Garbett & K Mirnics

  4. Kennedy Center for Research on Human Development,

    K Mirnics

  5. Vanderbilt University, Nashville, TN, USA

    K Mirnics

  6. Department of Child Neuropsychiatry, II University of Naples, Naples, Italy

    R Militerni

  7. Department of Child Neuropsychiatry, University ‘Federico II’, Naples, Italy

    C Bravaccio

  8. Department of Child Neuropsychiatry, University ‘Tor Vergata’, Rome, Italy

    P Curatolo & B Manzi

  9. Center for Autism Research and Education, Phoenix, AZ, USA

    C Schneider

  10. Southwest Autism Research and Resource Center, Phoenix, AZ, USA

    R Melmed

  11. Unit of Neurology and Clinical Neurophysiopathology, I.R.C.C.S. ‘Oasi Maria S.S.’, Troina (EN), Italy

    M Elia

  12. Department of Psychology, University ‘La Sapienza’, Rome, Italy

    T Pascucci & S Puglisi-Allegra

  13. Department of Experimental Neurosciences, Laboratory of Behavioral Neurobiology, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy

    T Pascucci & S Puglisi-Allegra

  14. Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway

    K-L Reichelt

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  1. C Lintas
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Correspondence to A M Persico.

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Lintas, C., Sacco, R., Garbett, K. et al. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry 14, 705–718 (2009). https://doi.org/10.1038/mp.2008.21

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