Two genetic variants of CD38 in subjects with autism spectrum disorder and controls

Abstract

34 These authors contributed equally to the work.Key Words: CD38, oxytocin, mutation, polymorphism, autism, high-functioning autism Author information Correspondence and requests for materials should be addressed to H. Higashida (haruhiro@med.kanazawa-u.ac.jp). 3 ABSTRACTThe neurobiological basis of autism spectrum disorder (ASD) remains poorly understood.Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons.In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6%-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.4

Are retinoids potential therapeutic agents in disorders of social cognition including autism?

“…The results shown in the Table are significant (p < 0.05) following permutation testing. Importantly, the SNP (and the 'C' allele) identified in the Munesue et al study [68] (rs3796863), which they found significantly associated with ASD, is located in all except one of the significant haplotypes in our study.…”

“…The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort [68] OT plasma levels were lower in subjects with the T allele than in those without.…”

“…Notably, the potential of CD38 expression as a diagnostic indicator for ASD was a hypothesis driven idea catalyzed by the seminal study of Higashida and his colleagues [59] in the CD38 knockout mouse and reinforced by two independent molecular genetic studies showing association between SNPs in the CD38 gene and ASD [68,69].…”

All-trans Retinoic Acid Upregulates Reduced CD38 Transcription in Lymphoblastoid Cell Lines from Autism Spectrum Disorder

“…Notably, CD38 is highly expressed in the human hypothalamus (21), and is colocalized with oxytocinergic neuronal structures, the apparent source of OT in the brain (22). Moreover, two independent groups have demonstrated associations between CD38 single-nucleotide polymorphisms (SNPs) and ASD (21,23).…”

Dual Roles of CD38 in Autophagy

“…Moreover, CD38 contains some variations in single nucleotide that occur at specific sites in the genome, called single-nucleotide polymorphisms (SNPs), which have been used in genome-wide association studies (GWAS) as a key marker in gene mapping related to human diseases. The SNP position of CD38 at residues R140 (corresponding to rs1800561) is closely related to ASD or type II diabetes [9] [11]. Another SNP site rs6449182 at P184 is associated with richter syndrome [9] [10] [11].…”