title: A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness.
abstract: OBJECTIVE
  Leptin, a protein product of adipocytes, plays a critical role in the regulation of body weight, immune function, pubertal development, and fertility. So far, only three homozygous mutations in the leptin gene in a total of 13 individuals have been found leading to a phenotype of extreme obesity with marked hyperphagia and impaired immune function.
  
  
  METHODS
  Serum leptin was measured by ELISA. The leptin gene (OB) was sequenced in patient DNA. The effect of the identified novel mutation was assessed using HEK293 cells.
  
  
  RESULTS
  We describe a 14-yr-old child of nonobese Austrian parents without known consanguinity. She had a body mass index of 31.5 kg/m(2) (+2.46 SD score) and undetectable leptin serum levels. Sequencing of the leptin gene revealed a hitherto unknown homozygous transition (TTA to TCA) in exon 3 of the LEP gene resulting in a L72S replacement in the leptin protein. RT-PCR, Western blot, and immunohistochemical analysis indicated that the mutant leptin was expressed in the patient's adipose tissue but retained within the cell. Using a heterologous cell system, we confirmed this finding and demonstrated that the side chain of Leu72 is crucial for intracellular leptin trafficking. Our patient showed signs of a hypogonadotropic hypogonadism. However, in contrast to the literature, she showed only mild obesity and a normal T cell responsiveness.
  
  
  CONCLUSIONS
  These findings shed a new light on the clinical consequences of leptin deficiency. Congenital leptin deficiency should be considered possible in pediatric patients with mild obesity even if parents are lean and unrelated.
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University of Ulm, Eythstrasse 24, 89075 Ulm, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.forename: Julia
authors.initials: J
authors.lastname: von Schnurbein
authors.forename: Barbara
authors.initials: B
authors.lastname: Moepps
authors.forename: Georgia
authors.initials: G
authors.lastname: Lahr
authors.forename: Gudrun
authors.initials: G
authors.lastname: Strauss
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Barth
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.forename: Hannes
authors.initials: H
authors.lastname: Mühleder
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
mesh_terms: D050154:Adiposity / Q000235:genetics; D000293:Adolescent; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D049109:Cell Proliferation; D003001:Cloning, Molecular; D003080:Cold Temperature; D016207:Cytokines / Q000097:blood; D018076:DNA, Complementary / Q000235:genetics; D004435:Eating / Q000502:physiology; D002149:Energy Intake; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007150:Immunohistochemistry; D020738:Leptin / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D009043:Motor Activity / Q000502:physiology; D020125:Mutation, Missense / Q000235:genetics*; D009765:Obesity / Q000178:diet therapy / Q000235:genetics*; D011312:Pressure; D013601:T-Lymphocytes / Q000502:physiology*; D014162:Transfection
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D020738:Leptin