Endocrine Abstracts (2009) 20 P472

Melanocortin-4-receptor gene variants: hotspot or identical by descent?

Jessica Grothe1, Harald Brumm1, André Scherag4, Susann Friedel3, Anke Hinney3, Johannes Hebebrand3, Thomas Illig2, Harald Grallert2, Susanna Wiegand1, Heiko Krude1, Sadaf Farooqi5, Annette Grüters1 & Heike Biebermann1


1Institute of Experimental Pediatric Endocrinology, Charité Campus Virchow-Klinikum, Berlin, Germany; 2Helmholtz Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, München, Germany; 3Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Essen, Germany; 4Institut für Medizinische Informatik, Biometrie und Epidemiologie Universitätsklinikum Essen, Essen, Germany; 5Metabolic Research Laboratories, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK.


The melanocortin-4-receptor (MC4R) plays an important role in body weight regulation. Mutations in the MC4R gene are the most common genetic cause for obesity. The most frequent Northern European mutation is Y35X, associated with D37V on the same allele. Furthermore, there are two variants with a relatively high frequency: V103I and S127L. In rare cases, we identified the variants V103I and S127L on the same allele. The occurrence of two variants on the same allele makes a founder effect possible but this has yet to be proven. Therefore, we analysed single nucleotide polymorphisms (SNPs) within a range of overall 240 kb up- and downstream of the MC4R gene. Our sample group consisted of a healthy control group and of trios of normal weight and obese patients of Caucasian origin. We analysed 25 mutation carriers of Y35X/D37V, three V103I/S127L carriers and their families and two Arab families each with two homozygous carriers of a pathogenic missense mutation, C271R.

Linkage disequilibrium (LD) analyses show that the investigated SNPs form three different LD-blocks. In a first attempt we focused on those SNPs forming an LD-block that comprises the coding region of the MC4R gene for haplotype analysis. Aside from 11 different haplotypes we found one main haplotype with a frequency of approximately 73% in the control trios. Via analysis of the mutation carriers we could show that the Y35X/D37V mutation is estimated to be always located on this common haplotype making a founder effect highly possible. The double mutation V103I/S127L is located on another haplotype as well as the C271R mutation which indicate identity by decent. In conclusion, we can show that the increased prevalence of certain MC4R mutations, Y35X/D37V and V103I/S127L in Caucasian and C271R in patients of Arab origin, can be attributed to a founder effect in these populations.