title: Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.
abstract: The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5' end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
authors.affiliation: University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 2XY, U.K.
authors.forename: Juliette
authors.initials: J
authors.lastname: Gray
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.forename: Anna-Lynne R
authors.initials: AL
authors.lastname: Adlam
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
authors.forename: Areeg
authors.initials: A
authors.lastname: El Gharbawy
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
authors.forename: Y C Loraine
authors.initials: YC
authors.lastname: Tung
authors.forename: John R
authors.initials: JR
authors.lastname: Hodges
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Stephen
authors.initials: S
authors.lastname: O'rahilly
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D000328:Adult; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000235:genetics*; D002869:Chromosome Aberrations; D007446:Chromosome Inversion / Q000235:genetics*; D022202:Chromosomes, Artificial, Bacterial; D003072:Cognition Disorders / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics*; D006963:Hyperphagia / Q000235:genetics*; D009154:Mutation; D009765:Obesity / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004247:DNA