title: Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research, University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom. isf20@cam.ac.uk
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Teresia
authors.initials: T
authors.lastname: Wangensteen
authors.forename: Stephan
authors.initials: S
authors.lastname: Collins
authors.forename: Wendy
authors.initials: W
authors.lastname: Kimber
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Emma
authors.initials: E
authors.lastname: Lank
authors.forename: Bill
authors.initials: B
authors.lastname: Bottomley
authors.forename: Judith
authors.initials: J
authors.lastname: Lopez-Fernandez
authors.forename: Ivan
authors.initials: I
authors.lastname: Ferraz-Amaro
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: Oya
authors.initials: O
authors.lastname: Ercan
authors.forename: Anne Grethe
authors.initials: AG
authors.lastname: Myhre
authors.forename: Lars
authors.initials: L
authors.lastname: Retterstol
authors.forename: Richard
authors.initials: R
authors.lastname: Stanhope
authors.forename: Julie A
authors.initials: JA
authors.lastname: Edge
authors.forename: Sheila
authors.initials: S
authors.lastname: McKenzie
authors.forename: Nader
authors.initials: N
authors.lastname: Lessan
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghodsi
authors.forename: Veronica
authors.initials: V
authors.lastname: De Rosa
authors.forename: Francesco
authors.initials: F
authors.lastname: Perna
authors.forename: Silvia
authors.initials: S
authors.lastname: Fontana
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Dag E
authors.initials: DE
authors.lastname: Undlien
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D000328:Adult; D017668:Age of Onset; D001481:Basal Metabolism; D001823:Body Composition; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006801:Humans; D006963:Hyperphagia / Q000097:blood / Q000150:complications / Q000235:genetics; D007006:Hypogonadism / Q000097:blood / Q000150:complications / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000150:complications / Q000235:genetics; D020738:Leptin / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics*; D054411:Receptors, Leptin
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin