Title
Identification and functional characterization of novel mutations in the melanocortin-4 receptorIdentification and functional characterization of novel mutations in the melanocortin-4 receptor
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
Laboratory Experimental Medicine and Pediatrics (LEMP)
Laboratory of cell biology and histology
Human molecular genetics
Medical genetics of obesity and skeletal disorders (MGENOS)
Department of Biomedical Sciences
Publication type
article
Publication
Subject
Human medicine
Source (journal)
Obesity facts
Volume/pages
3(2010):5, p. 304-311
ISSN
1662-4033
ISI
000283546800005
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Objective: Melanocortin-4 receptor (MC4R) deficiency is the most common cause of monogenic obesity. In the present study, we screened the MC4R gene for mutations in a population of overweight and obese children and adolescents. Method: Cross-sectional mutation analysis of 112 overweight/obese children and adolescents and 121 lean individuals. Results: We identified 11 sequence variations, 5 of which were present in our control population or had been previously reported as polymorphisms. The remaining 6 variations are disease-causing mutations including 2 novel ones: a I186V mutation and a F280L mutation. The 4 previously described mutations (D90N, M200V, P260Q, Q307X) were identified in single probands. Using confocal imaging, we demonstrated that F280L and P260Q cause intracellular retention of the mutant receptor. No difference in cell surface expression could be detected for the I186V mutation. Using a cAMP responsive luciferase vector, we demonstrated that the receptor with I186V is unable to activate its intracellular signaling pathway while the P260Q mutation causes reduced activation of the receptor. Conclusion: We detected MC4R deficiency in 6 patients from our cohort, amounting to a prevalence of 5.3%. Two novel mutations were identified. We also confirmed that intracellular retention is a common pathogenic effect of MC4R mutations.
E-info
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