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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.

A Heterozygous Mutation in the Third Transmembrane Domain Causes a Dominant-Negative Effect on Signalling Capability of the MC4R