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Title: A PYY Q62P variant linked to human obesity

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Director. Office of Science. Office of Biological andEnvironmental Research; GlaxoSmithKline Grant NA5413, Heart and StrokeFoundation of Ontario NA5413
OSTI Identifier:
888763
Report Number(s):
LBNL-57937
R&D Project: 626809; BnR: KP1103010; TRN: US200622%%129
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
Human Molecular Genetics
Additional Journal Information:
Journal Volume: 15; Journal Issue: 3; Related Information: Journal Publication Date: 02/01/2006
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CELL CULTURES; EXONS; FOOD; FUNCTIONAL ANALYSIS; GENES; METABOLIC DISEASES; NUCLEOTIDES; PEPTIDES; POLYPEPTIDES; RODENTS; SEGREGATION

Citation Formats

Ahituv, Nadav, Kavaslar, Nihan, Schackwitz, Wendy, Ustaszewska, Anna, Collier, John Michael, Hebert, Sybil, Doelle, Heather, Dent, Robert, Pennacchio, Len A, and McPherson, Ruth. A PYY Q62P variant linked to human obesity. United States: N. p., 2005. Web. doi:10.1093/hmg/ddi455.
Ahituv, Nadav, Kavaslar, Nihan, Schackwitz, Wendy, Ustaszewska, Anna, Collier, John Michael, Hebert, Sybil, Doelle, Heather, Dent, Robert, Pennacchio, Len A, & McPherson, Ruth. A PYY Q62P variant linked to human obesity. United States. https://doi.org/10.1093/hmg/ddi455
Ahituv, Nadav, Kavaslar, Nihan, Schackwitz, Wendy, Ustaszewska, Anna, Collier, John Michael, Hebert, Sybil, Doelle, Heather, Dent, Robert, Pennacchio, Len A, and McPherson, Ruth. 2005. "A PYY Q62P variant linked to human obesity". United States. https://doi.org/10.1093/hmg/ddi455. https://www.osti.gov/servlets/purl/888763.
@article{osti_888763,
title = {A PYY Q62P variant linked to human obesity},
author = {Ahituv, Nadav and Kavaslar, Nihan and Schackwitz, Wendy and Ustaszewska, Anna and Collier, John Michael and Hebert, Sybil and Doelle, Heather and Dent, Robert and Pennacchio, Len A and McPherson, Ruth},
abstractNote = {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.},
doi = {10.1093/hmg/ddi455},
url = {https://www.osti.gov/biblio/888763}, journal = {Human Molecular Genetics},
number = 3,
volume = 15,
place = {United States},
year = {Mon Jun 27 00:00:00 EDT 2005},
month = {Mon Jun 27 00:00:00 EDT 2005}
}