A heterozygous mutation in the third transmembrane domain causes a dominant-negative effect on signalling capability of the MC4R.

ABSTRACT:

Background

Heterozygous MC4R mutation is the most frequent cause of monogenic obesity. For most MC4R mutations a gene dosage effect seems to be the underlying mechanism. However, a dominant negative effect of a heterozygous MC4R mutation was recently identified, pointing to an additional mechanism of MC4R inactivation.

Methods

The complete loss-of-function mutation (Ser136Phe), identified in a cohort of obese Austrian patients, was characterized for cell surface expression, signal transduction and ligand binding properties. Co-transfection studies tested for a dominant negative effect. Dimerization was investigated by a sandwich ELISA and by fluorescence resonance energy transfer (FRET) approach. Potential intramolecular interactions of Ser136 were studied by homologous rece

SUBMITTER: Tarnow P 

PROVIDER: S-EPMC6452123 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature