Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany.
BACKGROUND
Autosomal dominant inheritance of mutations in the melanocortin-4 receptor gene (MC4R) is currently regarded as the most relevant genetic cause for extreme obesity and affects 2-4% of extremely obese individuals.


OBJECTIVE
Our objective was to assess the relevance of MC4R mutations in a German population-based sample.


METHODS
We conducted a mutation screen of the MC4R gene by capillary electrophoresis-based single-strand conformation polymorphism analysis and denaturing HPLC.


METHODS
Subjects included 4068 individuals of a German population-based study group [Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA-S4); i.e. Cooperative Health Research in the Region of Augsburg] and 1003 German obese adults (body mass index >or= 30 kg/m(2)).


METHODS
Samples with aberrant capillary electrophoresis-based single-strand conformation polymorphism analysis/denaturing HPLC patterns were resequenced. Functional studies including agonistic receptor stimulation (Nle-D-Phe-alpha-, alpha-, and beta-MSH) and cell surface expression assays were performed.


RESULTS
Sixteen (six novel) coding nonsynonymous mutations were detected in 27 heterozygous individuals of KORA-S4. Four of the mutation alleles led to impaired receptor function in vitro; however, none of these six heterozygous mutation carriers was obese (body mass index >or= 30 kg/m(2)). In the obese adults, six coding nonsynonymous and a nonsense mutation were detected in 13 individuals. Only the nonsense mutation allele entailed impaired receptor function.


CONCLUSIONS
Our study depicts prevalence, spectrum, and functional characterization of MC4R mutations in the German population-based sample KORA-S4. In this epidemiological study group, individuals heterozygous for nonsynonymous MC4R mutation alleles entailing impaired function were not obese. Furthermore, nonsynonymous MC4R mutations causing impaired receptor function were rare in German obese adults (two in 1003 = 0.2%).
Hinney
Anke
A
Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Virchowstrasse 174, 45147 Essen, Germany. anke.hinney@uni-duisburg-essen.de
Bettecken
Thomas
T
Tarnow
Patrick
P
Brumm
Harald
H
Reichwald
Kathrin
K
Lichtner
Peter
P
Scherag
André
A
Nguyen
Thuy Trang
TT
Schlumberger
Pia
P
Rief
Winfried
W
Vollmert
Caren
C
Illig
Thomas
T
Wichmann
H-Erich
HE
Schäfer
Helmut
H
Platzer
Matthias
M
Biebermann
Heike
H
Meitinger
Thomas
T
Hebebrand
Johannes
J
D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044105:Receptor, Melanocortin, Type 4 / Q000008:administration & dosage / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D044105:Receptor, Melanocortin, Type 4