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1.
Mol Med ; 17(7-8): 799-806, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21528155

RESUMO

Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.


Assuntos
ADP-Ribosil Ciclase 1/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Linfócitos/efeitos dos fármacos , Tretinoína/farmacologia , Adolescente , Adulto , Linhagem Celular , Criança , Transtornos Globais do Desenvolvimento Infantil/patologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Pré-Escolar , Ilhas de CpG/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Humanos , Inteligência/genética , Íntrons/genética , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elementos de Resposta/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
2.
Autism Res ; 3(6): 293-302, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21182206

RESUMO

BACKGROUND: Impairments in social processes characterize one of the core deficits in autism spectrum disorders (ASD) and accumulating evidence suggests that oxytocin neurotransmission is implicated in mediating social adaptation in ASD. Using a mouse model, CD38, a transmembrane protein expressed in immune cells but also in brain, was found to be critical for social behavior via regulation of oxytocin secretion. This prompted us to both examine CD38 expression in human lymphoblastoid cell lines (LBC) as well as to test association between SNPs across the CD38 gene and ASD. METHODS: LBC's were derived from 44 ASD lines and 40 "unaffected" parents. Family-based association (UNPHASED) was examined by genotyping 11 tagging SNPs spanning the CD38 gene identified using HapMap data in 170 trios. An additional SNP (rs3796863) associated in a study by Munesue et al. with ASD was also genotyped. RESULTS: A highly significant reduction in CD38 expression was observed in immortalized lymphocytes derived from ASD subjects compared to their "unaffected" parents (F517.2, P50.00024, df51). Haplotype analysis showed significant association (permutation corrected) between three and seven locus haplotypes and DSM IV ASD in low functioning (IQ < 70) subjects. CONCLUSIONS: The current report supports a role for CD38 in conferring risk for ASD. Notably, our study shows that this gene is not only associated with low functioning ASD but that CD38 expression is markedly reduced in LBC derived from ASD subjects compared to "unaffected" parents, strengthening the connection between oxytocin and ASD.


Assuntos
ADP-Ribosil Ciclase 1/genética , Transtorno Autístico/genética , Haplótipos/genética , Linfócitos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , ADP-Ribosil Ciclase 1/sangue , Adolescente , Adulto , Análise de Variância , Transtorno Autístico/sangue , Técnicas de Cultura de Células , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Humanos , Israel , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Adulto Jovem
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