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

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 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.

Autism genetics: Methodological issues and experimental design

“…Another vulnerability gene, MET, was identified by Campbell and Levitt collaborating with our group for the genetic studies involved in this project [80,81]. In addition, we have identified other new vulnerability genes and confirmed associations initially reported in other samples for several genes, including ADA [82], APOE [83], HOXA1 [84,85], ITG-B3 [86], PON1 [87], PRKCB1 [88], SLC6A4 [89,90], SLC-25A12 [91].…”

Linkage and candidate gene studies of autism spectrum disorders in European populations

“…These were NOSTRIN (nitric oxide synthase trafficker), 16 GRIK2 (glutamate receptor, ionotropic, kainite 2), 17,18 RELN, 9 PRKCB1 (protein kinase C, beta), 19,20 SLC6A4 (solute carrier family 5 (neurotransmitter transporter, serotonin), member 4), 21,22 SHANK3 (SH3 and multiple ankyrin repeat domains 3) 2,23 and ASMT (acetylserotonin O-methyltransferase). 24 …”

Immune Dysfunction in Autism: A Pathway to Treatment

“…These data suggest that genetic abnormalities in the MHC are not solely confined to HLA genes themselves, but also include genes in near proximity. In addition, a number of other immunerelated genes have been implicated in ASD, including macrophage migration inhibitory factor (MIF), 43 MET encoding tyrosine kinase, 44 the serine and threonine kinase C gene PRKCB (alias PRKCB1), 45 protein phosphatase and tensin homolog (PTEN), 46 and the reelin gene (RELN). [47][48][49] It is not known whether immune activation plays an initiating or ongoing role in the pathology of ASD.…”