Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case–control study in a Japanese population ... View Full Text


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Article Info

DATE

2013-07-01

AUTHORS

Wen-Jie Ma, Minako Hashii, Toshio Munesue, Kenshi Hayashi, Kunimasa Yagi, Masakazu Yamagishi, Haruhiro Higashida, Shigeru Yokoyama

ABSTRACT

BackgroundThe human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions.MethodsVariations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real-time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) levels.ResultsSix subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C>G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C>T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher’s exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher’s exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR-376C. In addition, the elevation in [Ca2+]i and IP3 formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR-376R tagged with EGFP.ConclusionsThese results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior. More... »

PAGES

22

References to SciGraph publications

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  • 2009-10-22. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism in BMC MEDICINE
  • 2011-10-30. The conundrums of understanding genetic risks for autism spectrum disorders in NATURE NEUROSCIENCE
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        "description": "BackgroundThe human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions.MethodsVariations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real-time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) levels.ResultsSix subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C>G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C>T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher\u2019s exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher\u2019s exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR-376C. In addition, the elevation in [Ca2+]i and IP3 formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR-376R tagged with EGFP.ConclusionsThese results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior.", 
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    20 schema:description BackgroundThe human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions.MethodsVariations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real-time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) levels.ResultsSix subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C>G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C>T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher’s exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher’s exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR-376C. In addition, the elevation in [Ca2+]i and IP3 formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR-376R tagged with EGFP.ConclusionsThese results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior.
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    26 schema:keywords ASD group
    27 ASD patients
    28 ConclusionsThese results
    29 G allele
    30 G genotype
    31 G variation
    32 HEK-293 cells
    33 IP3 formation
    34 Japan
    35 Japanese population
    36 Japanese volunteers
    37 Kanazawa University Hospital
    38 MethodsVariations
    39 OXT
    40 OXTR
    41 OXTR gene
    42 T allele
    43 T genotype
    44 University Hospital
    45 acid substitutions
    46 addition
    47 alleles
    48 amino acid substitutions
    49 analysis
    50 assays
    51 autism spectrum disorder
    52 basis
    53 behavior
    54 calcium concentration
    55 case-control study
    56 cells
    57 cellular responses
    58 changes
    59 comparison
    60 concentration
    61 control group
    62 correlation
    63 differences
    64 disorders
    65 elevation
    66 enhanced green fluorescent protein
    67 etiology
    68 fluorescent protein
    69 formation
    70 free calcium concentration
    71 frequency
    72 function
    73 functional analysis
    74 functional changes
    75 genes
    76 genetic variation
    77 genotypes
    78 genotyping
    79 green fluorescent protein
    80 group
    81 healthy Japanese volunteers
    82 heterozygotes
    83 hospital
    84 human oxytocin receptor
    85 human oxytocin receptor gene
    86 individual differences
    87 individuals
    88 inositol
    89 internalization
    90 intervention
    91 intracellular free calcium concentration
    92 levels
    93 likelihood
    94 likelihood of ASD
    95 measurements
    96 members
    97 modulation
    98 molecular basis
    99 non-synonymous single nucleotide variations
    100 oxytocin receptor
    101 oxytocin receptor gene
    102 pathogenesis
    103 pathogenesis of ASD
    104 patients
    105 polymerase chain reaction-based genotyping
    106 polymorphism
    107 population
    108 potential target
    109 protein
    110 protein-coding regions
    111 receptor function
    112 receptor gene
    113 receptor internalization
    114 receptors
    115 recycling
    116 region
    117 response
    118 results
    119 risk
    120 risk of ASD
    121 single nucleotide polymorphisms
    122 single nucleotide variations
    123 social behavior
    124 spectrum disorder
    125 study
    126 subjects
    127 substitution
    128 target
    129 therapeutic interventions
    130 trisphosphate levels
    131 unrelated healthy Japanese volunteers
    132 variation
    133 volunteers
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