One Single Nucleotide Polymorphism of the TRPM2 Channel Gene Identified as a Risk Factor in Bipolar Disorder Associates With Autism Spectrum Disorder in a Japanese Population

Toshio Munesue,Haruhiro Higashida,Naila Al Mahmuda,Chiharu Tsuji,Kenshi Hayashi,Kunimasa Yagi,Shigeru Yokoyama

doi:10.3390/diseases8010004

Abstract

The transient receptor potential melastatin 2 (TRPM2) is a non-specific cation channel, resulting in Ca2+ influx at warm temperatures from 34 °C to 47 °C, thus including the body temperature range in mammals. TRPM2 channels are activated by β-NAD+, ADP-ribose (ADPR), cyclic ADPR, and 2′-deoxyadenosine 5′-diphosphoribose. It has been shown that TRPM2 cation channels and CD38, a type II or type III transmembrane protein with ADP-ribosyl cyclase activity, simultaneously play a role in heat-sensitive and NAD+ metabolite-dependent intracellular free Ca2+ concentration increases in hypothalamic oxytocinergic neurons. Subsequently, oxytocin (OT) is released to the brain. Impairment of OT release may induce social amnesia, one of the core symptoms of autism spectrum disorder (ASD). The risk of single nucleotide polymorphisms (SNPs) and variants of TRPM2 have been reported in bipolar disorder, but not in ASD. Therefore, it is reasonable to examine whether SNPs or haplotypes in TRPM2 are associated with ASD. Here, we report a case-control study with 147 ASD patients and 150 unselected volunteers at Kanazawa University Hospital in Japan. The sequence-specific primer-polymerase chain reaction method together with fluorescence correlation spectroscopy was applied. Of 14 SNPs examined, one SNP (rs933151) displayed a significant p-value (OR = 0.1798, 95% CI = 0.039, 0.83; Fisher’s exact test; p = 0.0196). The present research data suggest that rs93315, identified as a risk factor for bipolar disorder, is a possible association factor for ASD.

Highlights

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disease [1,2,3]
Accumulation in the brain after peripheral application, it has recently been reported that the receptor for advanced glycation end products (RAGE) recruits OT from the blood circulation crossing over the blood–brain barrier, because RAGE is an OT-binding partner and carrier [57,58]
16 single nucleotide polymorphisms (SNPs) of transient receptor potential melastatin 2 (TRPM2) on human chromosome 21, whose physical locations are shown in Figure 1, were subjected to analysis in case–control association samples of the initial samples of cases and controls

Summary

Introduction

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disease [1,2,3]. the etiology accounting for ASD is not totally clear [1,4], it is understood that such neurodisorders are the result of a multitude of factors, including environmental factors and genetic susceptibility [5,6].Many studies have led to the identification of candidate genes whose variants and single nucleotideDiseases 2020, 8, 4; doi:10.3390/diseases8010004 www.mdpi.com/journal/diseasesDiseases 2020, 8, 4 polymorphisms (SNPs) might be associated with ASD [7,8]. A single administration of OT was revealed to have beneficial effects on social and emotional processes or impairments in both healthy subjects and individuals with a variety of psychiatric diseases, including ASD [23,24,25,26,27,28]. Repetitive administrations of OT into the nasal cavity of individuals with ASD results in the reduction of social behavioral impairment and increased episodes of social interaction in daily life [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. To support OT accumulation in the brain after peripheral application, it has recently been reported that the receptor for advanced glycation end products (RAGE) recruits OT from the blood circulation crossing over the blood–brain barrier, because RAGE is an OT-binding partner and carrier [57,58]

Results

Discussion

Conclusion