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Melanocortin-4 Receptor Gene: Case-Control Study and Transmission Disequilibrium Test Confirm that Functionally Relevant Mutations Are Compatible with a Major Gene Effect for Extreme Obesity

Clinical Research Group (A.H., C.V., A.-K.W., B.B., H.R., J.H.), Department of Child and Adolescent Psychiatry, Philipps-University of Marburg, D-35039 Marburg, Germany; Department of Pharmacology and Toxicology (S.H., C.H., T.G.), Philipps-University of Marburg, D-35033 Marburg, Germany; Institute of Medical Biometry and Epidemiology (F.G., H.S.), Philipps-University of Marburg, D-35037 Marburg, Germany; Spessart Klinik (H.G.), D-63619 Bad Orb, Germany; and Obesity Treatment Centre Insula (W.S.), D-83489 Berchtesgaden, Germany

Address all correspondence and requests for reprints to: Dr. Anke Hinney, Clinical Research Group, Department of Child and Adolescent Psychiatry, Philipps-University of Marburg, Schützenstr. 49, D-35039 Marburg, Germany. E-mail: anke.hinney{at}med.uni-marburg.de.

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher’s exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.

This work was supported by grants from the Deutsche Forschungsgesellschaft, Bundesministerium für Bildung und Forschung (01KW006; 01GS0118), and EU Framework V (Factors in Healthy Eating) (QLK1-CT-1999-00916).

Abbreviations: BMI, Body mass index; CI, confidence interval; SSCP, single-strand conformation polymorphism; TDT, transmission disequilibrium test; TEAA, triethylammonium acetate.

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