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A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity

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Abstract

This study targeted the identification of mutations of melanocortin-4 receptor gene (MC4R) in obese children. Fifty-one unrelated probands with early onset severe obesity (body mass index (BMI) >99th percentile; 21 girls, mean age 10.6 ± 3.6 years) were analyzed for nucleotide variations in the MC4R coding region, by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. MC4R variants were detected in three patients: the known I169S variant was found in heterozygote state in two patients and a novel heterozygous Y302F mutation was detected in one 12-year-old girl (BMI = 34 kg/m2, BMI z-score 2.7) who has been overweight since the second year of life and suffered from hyperinsulinemia (at the age of 12: fasting insulin 45 mU/ml, after oral glucose load max. 300 mU/ml). The mutation also appears in the father, although both parents are obese (BMI father: 30.2 kg/m2; mother: 31.9 kg/m2). This novel mutation is located in the functionally important NPXXY motif of the seventh transmembrane domain of the receptor. Functional characterization revealed reduction in cell surface expression and an alteration in signal transduction properties. These results add to the growing list of loss-of-function MC4R mutations in early onset obese patients and suggest an orexigenic effect of novel Y302F mutation.

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Acknowledgments

The authors thank O. Hiort for his help in establishing the SSCP, and K. Harz, R. Maslak, and S. Brezinski for their support in collecting and analyzing the data. This study was supported by the Bonfor Research Foundation, Bonn, Bonfor: O-119.0010, Germany, and the Deutsche Forschungsgemeinschaft SFB 577, TP A9, NGFN-2 01GS0492TP13 and NIH grant R15DK077213.

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Authors and Affiliations

  1. Division of Endocrinology, Seattle Children’s Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA, 98101, USA

    Christian L. Roth

  2. Institute of Clinical Biochemistry and Pharmacology, University of Bonn, Bonn, Germany

    Michael Ludwig

  3. Children’s Hospital, University of Bonn, Bonn, Germany

    Joachim Woelfle

  4. Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA

    Zhen-Chuan Fan & Ya-Xiong Tao

  5. Charite Campus Virchow, Institute of Experimental Pediatric Endocrinology, Berlin, Germany

    Harald Brumm & Heike Biebermann

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  1. Christian L. Roth
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  2. Michael Ludwig
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  3. Joachim Woelfle
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  4. Zhen-Chuan Fan
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  7. Ya-Xiong Tao
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Correspondence to Christian L. Roth.

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Roth, C.L., Ludwig, M., Woelfle, J. et al. A novel melanocortin-4 receptor gene mutation in a female patient with severe childhood obesity. Endocr 36, 52–59 (2009). https://doi.org/10.1007/s12020-009-9156-4

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