ESPE Abstracts (2015) 84 P-2-371

Prevalence and Phenotypic Characterization of MC4R Mutations in a Large Paediatric Cohort

Heike Vollbach, Stephanie Brandt, Georgina Lahr & Martin Wabitsch


Division of Paediatric Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Baden-Württemberg, Germany


Background: The melanocortin-4-receptor (MC4R) plays a key role in body weight regulation. Hypothalamic activation of MC4R reduces food intake and increases energy expenditure. Mutations in the MC4R gene lead to the most common cause of monogenetic obesity. More than 150 different mutations are currently known. Their prevalence in obese subjects differs between 0.2 and 5.8%, depending on ethnicity, age and grade of obesity of the analysed cohort. Impact on phenotype and metabolic characteristics is still debated; a MC4R syndrome with early onset obesity, increased linear growth and hyperinsulinaemia is claimed.

Objective and hypotheses: In a large German cohort of obese paediatric outclinic patients we aim to determine the prevalence and whether there is a specific phenotype as mentioned.

Method: 899 individuals were screened for coding MC4R mutations by DNA sequencing after PCR amplification. Further on statistical analysis of metabolic features and metrics traits was performed in the whole cohort and in a matched case–control setting. Individuals were matched for age, sex, and BMI–SDS.

Results: In total we found 22 carriers of heterozygous mutations (2.45%), of these 14 (1.56%) carriers had a mutation with impaired receptor function. One new nonsynonymous and one new frameshift mutation were detected. Regarding the whole cohort, mean height-SDS of MC4R deficient subjects was greater than of WT subjects at all ages. In matched individuals this trend persisted (eight of 11 pairs). No differences were found in glucose and insulin levels of matched pairs performing an oral glucose tolerance test.

Conclusion: Prevalence of mutations with impaired receptor function is comparable to other paediatric cohorts. MC4R deficiency tends to a taller stature, confirming previous clinical reports. This finding might be explained by decreased somatostatin mRNA expression like it is found in Agouti-related protein overexpressing mice. Hence GH secretion is possibly not as suppressed as normally seen in obesity.

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