TY - JOUR
T1 - All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from autism spectrum disorder
AU - Riebold, Mathias
AU - Mankuta, David
AU - Lere, Elad
AU - Israel, Salomon
AU - Zhong, Songfa
AU - Nemanov, Luba
AU - Monakhov, Mikhail V.
AU - Levi, Shlomit
AU - Yirmiya, Nurit
AU - Yaari, Maya
AU - Malavasi, Fabio
AU - Ebstein, Richard P.
N1 - Funding Information:
We thank Autism Speaks for partial support of this research (RP Ebstein) as well as support (F Malavasi) by AIRC (Special Program Molecular and Clinical Oncology 5×1000) and by the Fondazione Internazionale Ricerca Medicina Speri-mentale (FIRMS).
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960720036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960720036&partnerID=8YFLogxK
U2 - 10.2119/molmed.2011.00080
DO - 10.2119/molmed.2011.00080
M3 - Article
C2 - 21528155
AN - SCOPUS:79960720036
SN - 1076-1551
VL - 17
SP - 799
EP - 806
JO - Molecular Medicine
JF - Molecular Medicine
IS - 7-8
ER -