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Clinical Research Group, Department of Child and Adolescent Psychiatry (A.H., A.S., K.N., O.H., I.B., G.G., M.S., H.R., J.H.), University of Marburg, 35033 Marburg; Institute of Medical Biometry and Epidemiology (A.Z., T.G.), University of Marburg, Marburg; Children’s Hospital Hochried (H.M.), Murnau; Obesity Treatment Center Insula (W.S.), Berchtesgaden; Klinik Roseneck (M.F.), Prien, Germany
Abstract
The melanocortin-4 receptor gene (MC4-R) has been implicated
in weight regulation. Recently, two independent groups reported
frameshift mutations associated with a dominant form of obesity
(1, 2). We screened the coding region of the MC4-R in
306 extremely obese children and adolescents (mean body mass index: BMI
34.4 ± 6.6 kg/m2), 25 healthy underweight students (mean
BMI 17.1 ± 0.8 kg/m2), 52 normal weight individuals (mean
BMI 22.0 ± 1.0 kg/m2), 51 inpatients with anorexia nervosa
(AN, DSM IV criteria, mean BMI 14.3 ± 1.5 kg/m2) and 27
patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 ±
5.8 kg/m2) by single strand conformation polymorphism
analysis (SSCP). Several mutations were identified, including the
frameshift mutation described (1). The mutations were as follows: a)
The deletion of 4 bp (
of CTCT at codon 211) results in a
frameshift, thus rendering a truncated protein. This mutation has been
assumed to be associated with dominantly-inherited morbid obesity in
humans (1). Both the index patient (BMI 42.06 kg/m2, height
171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2,
height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A
nonsense mutation at position 35 of the MC4-R was detected
in two obese probands (BMI 31.29 kg/m2 and BMI 45.91
kg/m2). This mutation leads to a truncated protein that
encompasses the N-terminal extracellular domain. Both carriers
additionally showed (c) a missense mutation (Asp-37-Val). In both of
these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted,
thus these variations form a haplotype. d) e) A male obese proband
harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)–i) Four
different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp,
Ile-317-Thr) were detected in four different male probands,
respectively. All of these mutations (a to i) were found solely in
extremely obese individuals whose BMIs were all above the 99th
percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in
a male underweight individual. k) A previously described polymorphism
(Val-103-Ile; 3) was detected with similar frequencies in all different
study groups. l) We identified a novel polymorphism (Ile-251-Leu) with
similar allele frequencies in all groups under study. In conclusion,
our data indicate that mutations in the MC4-R are not
uncommon. Whereas our data support the evidence for dominantly
inherited obesity as revealed by the three obese probands with
haplo-insufficiency, the functional significance of the missense
mutations remains to be determined.
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