A PYY Q62P variant linked to human obesity.
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.
Ahituv
Nadav
N
Genomics Division, One Cyclotron Road, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Kavaslar
Nihan
N
Schackwitz
Wendy
W
Ustaszewska
Anna
A
Collier
John Michael
JM
Hébert
Sybil
S
Doelle
Heather
H
Dent
Robert
R
Pennacchio
Len A
LA
McPherson
Ruth
R
D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D019894:Peptide YY / Q000235:genetics*; D019518:Postprandial Period; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D019894:Peptide YY