Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor

I. Sadaf Farooqi, Teresia Wangensteen, Stephan Collins, Wendy Kimber, Giuseppe Matarese, Julia M. Keogh, Emma Lank, Bill Bottomley, Judith Lopez-Fernandez, Ivan Ferraz-Amaro, Mehul T. Dattani, Oya Ercan, Anne Grethe Myhre, Lars Retterstol, Richard Stanhope, Julie A. Edge, Sheila McKenzie, Nader Lessan, Maryam Ghodsi, Veronica De RosaFrancesco Perna, Silvia Fontana, Inês Barroso, Dag E. Undlien, Stephen O'Rahilly

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)237-247
Number of pages11
JournalNew England Journal of Medicine
Issue number3
Publication statusPublished - Jan 18 2007

ASJC Scopus subject areas

  • Medicine(all)


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