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 beta II isoenzymes result from the alternative splicing of the PKC beta 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 PKC beta II 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 PKC beta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKC beta 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 PKC beta 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
Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression / Lintas, C.; Sacco, R.; Garbett, K.; Mirnics, K.; Militerni, R.; Bravaccio, C.; Curatolo, P.; Manzi, B.; Schneider, C.; Melmed, R.; Elia, M.; Pascucci, Tiziana; PUGLISI ALLEGRA, Stefano; Reichelt, K. L.; Persico, A. M.. - In: MOLECULAR PSYCHIATRY. - ISSN 1359-4184. - 14:7(2009), pp. 705-718. [10.1038/mp.2008.21]
Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression
R. Sacco;PASCUCCI, Tiziana;PUGLISI ALLEGRA, Stefano;
2009
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 beta II isoenzymes result from the alternative splicing of the PKC beta 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 PKC beta II 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 PKC beta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKC beta 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 PKC beta 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 2008I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
