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


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.

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Figure 1: Identification of a de novo mutation in TrkB.
Figure 2: Phenotype of 8-year-old boy with the Y722C mutant TrkB.


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This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., J.R. and S.O.R.) and the Medical Research Council (J.G., J.K. and S.O.R.). We are indebted to the patients and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS).

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Correspondence to Stephen O'Rahilly.

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Yeo, G., Connie Hung, CC., Rochford, J. et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7, 1187–1189 (2004).

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