A PYY Q62P variant linked to human obesity
Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysis of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director. Office of Science. Office of Biological andEnvironmental Research; GlaxoSmithKline Grant NA5413, Heart and StrokeFoundation of Ontario NA5413
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 888763
- Report Number(s):
- LBNL-57937; R&D Project: 626809; BnR: KP1103010; TRN: US200622%%129
- Journal Information:
- Human Molecular Genetics, Vol. 15, Issue 3; Related Information: Journal Publication Date: 02/01/2006
- Country of Publication:
- United States
- Language:
- English
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