A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

• Published in: Nature neuroscience Vol. 7; no. 11; pp. 1187 - 1189
• Main Authors: O'Rahilly, Stephen, Yeo, Giles S H, Connie Hung, Chiao-Chien, Rochford, Justin, Keogh, Julia, Gray, Juliette, Sivaramakrishnan, Shoba, Farooqi, I Sadaf
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-11-2004
• Subjects: Age Factors; Animals; Blotting, Western - methods; Body Mass Index; Body Weight - genetics; Brain-Derived Neurotrophic Factor - pharmacology; Child; Complications and side effects; COS Cells - metabolism; Cysteine - genetics; Developmental Disabilities - complications; Developmental Disabilities - genetics; DNA Mutational Analysis - methods; Eating; Fluorescent Antibody Technique - methods; Gene Expression Regulation - drug effects; Gene mutations; Genetic aspects; Humans; Male; MAP Kinase Signaling System - genetics; Memory Disorders - etiology; Memory Disorders - genetics; Memory, Disorders of; Mutation, Missense; Neural receptors; Obesity; Obesity - complications; Obesity - genetics; PC12 Cells - drug effects; PC12 Cells - metabolism; Phosphorylation; Physiological aspects; Rats; Receptor, trkB - genetics; Risk factors; Transfection - methods; Tyrosine - genetics; United Kingdom
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn1336

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.