Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor

By I. Farooqi, T. Wangensteen, S. Collins, Wendy A. Kimber, G. Matarese, J. Keogh, E. Lank, B. Bottomley, Judith López-Fernández, I. Ferraz-Amaro and 15 more. New England Journal of Medicine, 2007

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BACKGROUND A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations — 7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/c208d0850ab8611f8e19a19b96c84efd3505e698

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Citations in the corpus

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Narrative Review: The Role of Leptin in Human Physiology: Emerging Clinical Applications (2010, background): “Clinically, patients with congenital leptin deficiency caused by mutations in the leptin gene or extreme leptin resistance caused by mutations of the leptin-receptor gene are obese because of marked hyperphagia (31, 32).”
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