Abstract
We have previously demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin(OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in CD38 knockout mice. The autism spectrum disorders(ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. The etiology of ASDs remains largely unknown and pharmacological treatments are needed. Therefore, we investigated single nucleotide polymorphisms(SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 was associated with high-functioning autism(HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561, leads to the substitution of an arginine(R) at codon 140 by tryptophan(W; R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. Our preliminary study reveals that one proband with the R140W allele or 3 other ASD patients out of 6 receiving intranasal OXT for 0.5-3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials. Further studies are necessary how intranasal OXT gets into the brain bypassing the blood-brain barrier.
