Functional Rescue of Obesity-causing Human Melanocortin-4 Receptor Mutants: Insights for Pharmacological Chaperon Drugs

Copyright: © 2013 Dong B et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. In the past decade, mammalian and human genetic studies revealed that the leptin-regulating pathway plays a critical role in controlling body weight. So far, it has been demonstrated that mutation in seven genes including Leptin (LEP), Leptin Receptor (LEPR), Prohormone 1 (PC1), Pro-Opiomelanocortin (POMC), Melanocortin-4 Receptor (MC4R), and Single-Minded Homolog 1 (SIM1) cause monogenic early-onset obesity for both rodent and human [1]. Among them, MC4R has been identified as a key switch in the leptin-regulating pathway [2-6]. Mutations occurred in the coding region of the MC4R gene represent the most frequent monogenetic form causing human early-onset obesity and thus serve as the best available genetic model to investigate human obesity [7-9]. So far, over 150 mutant MC4Rs has been identified clinically from obese patients of variant ethnic backgrounds and around 6% of the human early-onset obesity was estimated to be caused by the mutated MC4Rs. Functional studies showed that 70% of the mutant MC4Rs are synthesized normally but defective in trafficking onto the cell surface, thus representing the most common defect of mutant MC4Rs [7].