Severe early-onset obesity
Gene: MRAP2
Comment on list classification: Gene added by expert reviewer. Not associated with a phenotype/disease in Gene2Phenotype, Orphanet or HPO. In OMIM it is associated with susceptibility to obesity, marked with a question mark due to a report in one individual (PMID: 23869016), and in a literature study further support for this susceptibility was found in PMID: 27474872. MRAP2 knockout mice of both genders gradually became extremely obese on a diet of regular chow ad libitum (PMID: 23869016). PMID:23869016 and PMID:27474872 report variants in this gene in individuals with early-onset obesity, and a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients (PMID: 26795956). Evidence that disease-causing mutations follow a Mendelian parrern of causatiion appropriate for reporting in a diagnostic setting is still lacking, therefore this gene should be kept red (see notes regarding each publication...either segregation was not shown or family members were not available).Created: 17 Oct 2016, 10:27 a.m.
Source Expert list was added to MRAP2.
25/Oct/2016: Panel revised according to expert review and additional curation with internal discussion. Ready to be promoted to version 1.
This gene has been classified as Red List (Low Evidence).
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a 10-year old boy with overall obesity in combination with intellectual disability in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype. The clinically diagnosed PWS could not be confirmed molecularly with MS-MLPA and CNV analysis of the 6q14.1–q16.3 region also showed no deletions in this patient. No further family data were available to determine whether the variant segregates with obesity in this family. It was shown to be (probably) damaging by in silico analysis and found in only one European (non-Finnish) individual in the ExAC database (since this database cannot release phenotype information about the screened individuals, no conclusions regarding causality of this variant can be drawn).
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls, nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity, they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in we genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Publications for MRAP2 were set to 23869016 - sequenced the coding region and intron/exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity Study (GOOS) cohort and the Swedish obese children’s cohort. They describe identifying 4 heterozygous variants in 4 individuals with severe obesity, of which only one was predicted to be damaging (E24X); 27474872 - - screened the entire coding region of MRAP2 for mutations in 184 children and adolescents with extreme obesity and 184 healthy lean controls. Nonsynonymous variants were then genotyped in we genotyped in a larger, independent study group of 300 children and adolescents with extreme obesity and 436 controls. Detected variants were also analyzed in vitro to determine their effects on MC4R signaling: p.Gln174Arg was the only variant to show an effect by reducing MC4R signalling function. Heterozygous variants were described in 4 individuals. For only two (p.Ala137Thr and p.Arg125His) were relatives also available, and the mothers of the probands were also heterozygous and had not/did not display an obesity phenotype. "In sum, our family-based genetic data do not support the relevance of the two presumably benign MRAP2 mutations for the development of obesity; they might even have no influence on body weight regulation...additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations." "We detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher’ exact two-sided P<0.005) in a crude meta-analysis on all currently available data."; 26795956 - identified a rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene in a screen of Prader-Willi syndrome (PWS) patients, providing support for a possible role in the pathogenesis of the PWL phenotype.
Phenotypes for MRAP2 were set to obesity; {?Obesity, susceptibility to, BMIQ18};Prader-Willi syndrome
Publications for MRAP2 were set to 23869016; 27474872;26795956
Publications for MRAP2 were set to 23869016;27474872
This gene has been classified as Red List (Low Evidence).
Publications for MRAP2 were set to 23869016
Phenotypes for MRAP2 were set to obesity;{?Obesity, susceptibility to, BMIQ18}
This gene has been classified as Red List (Low Evidence).
MRAP2 was added to Significant early-onset obesity +/- other endocrine features and short staturepanel. Sources: Expert Review
MRAP2 was created by [email protected]