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A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

Nature volume 392, pages 398–401 (1998)Cite this article

Abstract

The adipocyte-specific hormone leptin, the product of the obese (ob) gene,regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure1,2,3,4. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family5,6,7. In rodents, homozygous mutations ingenes encoding leptin1 or the leptin receptor6 cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism8. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity9. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.

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Figure 1: Pedigree and clinical characteristics of the HD family, and analysis of exon 16 of the leptin receptor in this family.
Figure 2: SSCP scanning and DNA-sequence analysis of exon 16 of the human leptin receptor.
Figure 3: Height and weight curves for the three affected sisters from birth to adult age.

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Acknowledgements

This work was supported by the French Ministère de l'Education, de la Recherche etde la Technologie, the Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programme Hospitalier de Recherche Clinique and the Institut de Recherche Endocrinienne et Métabolique. We thank E. R. Serra, D. Pepin, S. Carrera, P. Boutin., L. Perrin, J. Le Fourn and Y. Le Bihan for technical help; J. Di Santo for critical reviewing of the manuscript; and the patients and their families for their cooperation. Informed personal and parental consents were obtained and ethical permission was granted by the local ethics committee (CCPPRB, Hôtel-Dieu, Paris).

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Author notes

  1. Karine Clément, Christian Vaisse, Jean Chambaz, Jean-Marc Lacorte and Pierre Bougnères: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Nutrition et Service de Médecine et Nutrition, Hôtel-Dieu place du Parvis Notre Dame, Paris, 75004, France

    Karine Clément, Christian Vaisse, Veronique Pelloux, Dominique Cassuto, Arnaud Basdevant, Philippe Froguel & Bernard Guy-Grand

  2. Institut de Biologie-CNRS EP10, Institut Pasteur de Lille, rue Calmette, Lille, 59000, France

    Karine Clément, Christian Vaisse, Christian Dina, Arnaud Basdevant, Philippe Froguel & Bernard Guy-Grand

  3. Inserm U342, Hôpital Saint Vincent de Paul et service d'Endocrinologie-Diabéte de l'Enfant, avenue Denfert Rochereau, Paris, 75014, France

    Najiba Lahlou

  4. Explorations fonctionnelles endocriniennes, Hôpital d'enfant Armand Trousseau, avenue du Dr Arnold Netter, Paris, 75012, France

    Sylvie Cabrol, Micheline Gourmelen & Yves Lebouc

  5. CJF INSERM 9508, 15 rue de l'Ecole de Médecine, Paris, 75005, France

    Jean Chambaz, Jean-Marc Lacorte & Pierre Bougnères

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  1. Karine Clément
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Correspondence to Philippe Froguel.

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Clément, K., Vaisse, C., Lahlou, N. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998). https://doi.org/10.1038/32911

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