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Involvement of the PRKCB1 Gene in Autistic Disorder

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Involvement of the PRKCB1 Gene in Autistic Disorder Molecular Psychiatry (2009) 14, 705–718 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp ORIGINAL ARTICLE Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression C Lintas1,2,14, R Sacco1,2,14, K Garbett3, K Mirnics3,4, R Militerni5, C Bravaccio6, P Curatolo7, B Manzi7, C Schneider8, R Melmed9, M Elia10, T Pascucci11,12, S Puglisi-Allegra11,12, K-L Reichelt13 and AM Persico1,2 1Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy; 2Laboratory of Molecular Psychiatry and Psychiatric Genetics, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy; 3Department of Psychiatry, Vanderbilt University, Nashville, TN, USA; 4Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA; 5Department of Child Neuropsychiatry, II University of Naples, Naples, Italy; 6Department of Child Neuropsychiatry, University ‘Federico II’, Naples, Italy; 7Department of Child Neuropsychiatry, University ‘Tor Vergata’, Rome, Italy; 8Center for Autism Research and Education, Phoenix, AZ, USA; 9Southwest Autism Research and Resource Center, Phoenix, AZ, USA; 10Unit of Neurology and Clinical Neurophysiopathology, I.R.C.C.S. ‘Oasi Maria S.S.’, Troina (EN), Italy; 11Department of Psychology, University ‘La Sapienza’, Rome, Italy; 12Laboratory of Behavioral Neurobiology, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy and 13Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway 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 bII isoenzymes result from the alternative splicing of the PKCb 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 PKCbII 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 PKCb-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCb 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 PKCb roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability. Molecular Psychiatry (2009) 14, 705–718; doi:10.1038/mp.2008.21; published online 4 March 2008 Keywords: autism; pervasive developmental disorders; PRKCB1; protein kinase C-b; temporal cortex; TGF-b Introduction social skills, and by repetitive and stereotypic behaviors.1 Family and twin studies support strong Autism is a severe neuropsychiatric disorder char- genetic contributions to this disease.2 However, the acterized by impaired language, communication and heterogeneity of clinical symptoms and the complex- ity of underlying pathogenetic processes have until Correspondence: Dr AM Persico, Laboratory of Molecular now undermined efforts to achieve reproducible Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, genotype–phenotype correlations. On one hand, the Via Alvaro del Portillo 21, I-00128 Rome, Italy. phenotypic expression of autism-predisposing genes E-mail: [email protected] 14These authors contributed equally to this study. spans from minimal autistic traits to full-blown Received 4 August 2007; revised 23 January 2008; accepted 23 autism, identifying a broad clinical entity referred to January 2008; published online 4 March 2008 as ‘autism-spectrum disorder’ (ASD).2,3 On the other PRKCB1 gene and autistic disorder C Lintas et al 706 hand, the genetic underpinnings of autism encompass system, PKCb isoenzymes play a critical role in B-cell significant interindividual heterogeneity, numerous receptor-mediated responses, T-cell migration and contributing loci, epistasis and likely gene–environ- cytokine secretion, dendritic cell differentiation and ment interactions.2 Incomplete penetrance (that is, monocyte and macrophage functioning.20–25 In the individuals carrying autism genes, but not fulfilling gut, PKCbI and bII are expressed by epithelial cells, diagnostic criteria for the ‘affected’ status) and where they regulate intestinal permeability and phenocopies (individuals carrying no genetic predis- cell proliferation, respectively.26–28 In the kidney, position and fulfilling diagnostic criteria for ‘autism’ both PKCb isoforms are expressed by mesangial cells solely due to environmental factors) further decrease and play a major role in diabetic nephropathy and the statistical power of genetic analyses by introdu- albuminuria, possibly through oxidative stress.29–31 cing false-negative and false-positive ‘affection status’ Interestingly, many of the non-neural signs and definitions. In this complex scenario, the probability symptoms that often accompany autism strikingly of success can be maximized by employing in parallel overlap with the pathophysiological roles played by both genetic analyses and postmortem assessments of PKCb isoforms in districts outside of the CNS. brain gene expression patterns. This strategy can The chromosomal region encompassing the PRKCB1 indeed promote a better understanding of single-gene locus was initially identified using a direct identity- contributions to complex disorders, as recently by-descent mapping method as one of seven regions demonstrated for the MET gene in autism.4,5 linked to autism, each spanning only between 0.75 and Several lines of evidence suggest that autism 4.0 Mb.14 The same study described an association should be viewed as a multiorgan systemic disorder between PRKCB1 gene variants and autism both with a prenatal onset. On one hand, autism does not in Caucasian-Americans and in Mexican-Americans, solely affect the central nervous system (CNS), albeit with the two ethnic groups carrying vulnerability despite encompassing obvious neurodevelopmental alleles marked by different haplotypes.14 This result components: systemic signs and symptoms include was later not replicated in an Irish sample (see macrosomy,6 excessive intestinal permeability and Discussion).32 Still, the presence of a significant genetic nonspecific enterocolitis,7–9 immune dysreactivity9 association in two different ethnic groups, coupled and renal oligopeptiduria.10 On the other hand, the with the functional involvement of PRKCB1 in many neurodevelopmental mechanisms underlying the pathophysiological processes potentially underlying CNS abnormalities found in postmortem studies, disease-related endophenotypes, spur interest into which include reduced programmed cell death and/ additional studies of PRKCB1 in autism. In accordance or increased cell proliferation, and altered neuronal with the strategy outlined above and previously migration, differentiation and synaptogenesis, with employed successfully with the MET gene,4,5 this study the exception of the latter, are all active prenatally, was designed to replicate the initial genetic findings especially during the first trimester of pregnancy.2,11,12 in an independent sample and to extend these studies Indeed, many children later diagnosed with ASD by (a) assessing PRKCB1 gene expression in postmortem display motor abnormalities13 and/or excessive body temporocortical gray matter (BA41/42) from 11 pairs of growth6 already on the day of birth or in early ASD patients and sex-, age-, and postmortem interval- neonatal life. Therefore, genes characterized by an matched controls; (b) correlating PRKCB1 gene expres- early onset of expression and encoding proteins sion with PRKCB1 genotypes in these postmortem brain involved in the control of cell division, differentiation samples and (c) assessing the functional consequences and migration can represent attractive candidates for of dysregulated PRKCB1 gene expression using genome- autistic disorder even if their tissue distribution wide expression array technology. Our results confirm patterns are not necessarily restricted to the CNS. the existence of a significant association between The PRKCB1 gene, located in human ch. 16p11.2, PRKCB1 gene variants and autism, describe for the first represents an interesting locus displaying expression time an association with the biochemical endopheno- patterns not restricted to the CNS and previously type defined by enhanced urinary peptide excretion found associated with autism.14 In general, protein rates, detect a significant
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