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Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function

Cedric Govaerts1, Supriya Srinivasan, Astrid Shapiro

  • 1Cellular and Molecular Pharmacology Department, University of California, San Francisco, CA 94143, USA.

Peptides
|August 9, 2005
PubMed

Insights

Mutations in the Melanocortin 4 receptor (MC4R) are linked to severe obesity. New assays reveal multiple functional defects in over 50 MC4R mutations, advancing our understanding of obesity genetics.

Area of Science:

  • Genetics
  • Molecular Biology
  • Endocrinology

Background:

  • Mutations in the Melanocortin 4 receptor (MC4R) are associated with 1-6% of early-onset or severe adult obesity.
  • Heterozygous missense mutations are common in affected patients.
  • Previous evidence for pathogenicity includes mutation frequency, family segregation, and observed functional defects.

Purpose of the Study:

  • To develop novel assays for studying obesity-associated MC4R mutations.
  • To conduct a systematic and comparative functional analysis of over 50 MC4R mutations.
  • To gain new insights into MC4R structure-function relationships and genetic predisposition to obesity.

Main Methods:

  • Development of new functional assays for MC4R.
  • Systematic and comparative functional characterization of >50 obesity-associated MC4R mutations.
  • Analysis of mutation frequency, family segregation, and functional defects.

Main Results:

  • Multiple functional alterations contribute to the pathogenicity of MC4R mutations.
  • Over 50 different obesity-associated mutations were functionally characterized.
  • New insights into MC4R structure-function relationships were obtained.

Conclusions:

  • Obesity-associated MC4R mutations exhibit diverse functional defects.
  • These findings provide novel hypotheses for the genetic basis of human obesity.
  • New molecular tools were developed for studying G protein-coupled receptors (GPCRs).

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