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Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(3):387-391; doi:10.1093/hmg/ddi455
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© The Author 2005. Published by Oxford University Press. All rights reserved.
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A PYY Q62P variant linked to human obesity

Nadav Ahituv1,2,{dagger}, Nihan Kavaslar3,{dagger}, Wendy Schackwitz1,2, Anna Ustaszewska2, John Michael Collier2, Sybil Hébert3, Heather Doelle3, Robert Dent3, Len A. Pennacchio1,2,* and Ruth McPherson3

1Genomics Division, One Cyclotron Road, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA, 2U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA and 3Division of Cardiology and Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Canada K1Y 4W7

* To whom correspondence should be addressed. Tel: +1 5104867498; Fax: +1 5104864229; Email: lapennacchio{at}lbl.gov

Received September 21, 2005; Accepted December 9, 2005

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n=379; average body mass index (BMI), 49.0 kg/m2] and lean (n=378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.

{dagger} These authors contributed equally to this work.


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