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Identification and functional analysis of novel human melanocortin-4 receptor variants

W Gu1, Z Tu, P W Kleyn

  • 1Millennium Pharmaceuticals, Cambridge, Massachusetts 02139, USA. gu@mpi.com

Diabetes
|March 17, 1999
PubMed

Insights

Genetic variations in the melanocortin-4 receptor (MC4-R) gene were studied in relation to obesity. A rare MC4-R variant showed impaired function, but overall, MC4-R gene changes are unlikely a common cause of obesity.

Area of Science:

  • Genetics
  • Endocrinology
  • Obesity Research

Background:

  • Melanocortin-4 receptor (MC4-R) gene inactivation in mice causes obesity and related metabolic disorders.
  • These mouse phenotypes mimic human late-onset obesity and non-insulin-dependent diabetes mellitus (NIDDM).
  • The role of MC4-R gene sequence variation in human obesity remains unclear.

Purpose of the Study:

  • To investigate the contribution of human MC4-R gene polymorphism to obesity.
  • To identify and functionally characterize MC4-R gene variants in obese individuals.

Main Methods:

  • Screening of the human MC4-R gene for polymorphisms in 190 individuals.
  • Cloning and in vitro expression of identified MC4-R variants.
  • Functional analysis of variants, including ligand binding and signaling assays.

Main Results:

  • Three allelic variants of the MC4-R gene were identified, including two novel variants: Thr112Met and Ile137Thr.
  • The Ile137Thr variant, found in an extremely obese individual, exhibited severely impaired ligand binding and signaling.
  • Sequence variations in the MC4-R coding region were found to be infrequent and unlikely to be a common cause of obesity in the studied population.

Conclusions:

  • A rare MC4-R variant (Ile137Thr) may contribute to obesity development due to impaired receptor function.
  • MC4-R gene sequence polymorphism is unlikely to be a widespread cause of obesity in the general population.

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