TY - JOUR
T1 - Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor
AU - Farooqi, I. Sadaf
AU - Wangensteen, Teresia
AU - Collins, Stephan
AU - Kimber, Wendy
AU - Matarese, Giuseppe
AU - Keogh, Julia M.
AU - Lank, Emma
AU - Bottomley, Bill
AU - Lopez-Fernandez, Judith
AU - Ferraz-Amaro, Ivan
AU - Dattani, Mehul T.
AU - Ercan, Oya
AU - Myhre, Anne Grethe
AU - Retterstol, Lars
AU - Stanhope, Richard
AU - Edge, Julie A.
AU - McKenzie, Sheila
AU - Lessan, Nader
AU - Ghodsi, Maryam
AU - De Rosa, Veronica
AU - Perna, Francesco
AU - Fontana, Silvia
AU - Barroso, Inês
AU - Undlien, Dag E.
AU - O'Rahilly, Stephen
PY - 2007/1/18
Y1 - 2007/1/18
N2 - 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.
AB - 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.
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U2 - 10.1056/NEJMoa063988
DO - 10.1056/NEJMoa063988
M3 - Article
C2 - 17229951
AN - SCOPUS:33846409122
VL - 356
SP - 237
EP - 247
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 3
ER -