TITLE

Prevalence of Loss of-Function FTO Mutations in Lean and Obese Individuals

AUTHOR(S)
Meyre, David; Proulx, Karine; Kawagoe-Takaki, Hiroko; Vatin, Vincent; Gutiérrez-Aguilar, Ruth; Lyon, Debbie; Ma, Marcella; Choquet, Helene; Horber, Fritz; Van Hul, Wim; Van Gaal, Luc; Balkau, Beverley; Visvikis-Siest, Sophie; Pattou, François; Farooqi, I. Sadaf; Saudek, Vladimir; O'Rahilly, Stephen; Froguel, Philippe; Sedgwick, Barbara; Yeo, Giles S. H.
PUB. DATE
January 2010
SOURCE
Diabetes;Jan2010, Vol. 59 Issue 1, p311
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
OBJECTIVE--Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto-/- mice are lean and Fro+/- mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO. RESEARCH DESIGN AND METHODS--We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants. RESULTS--We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals. CONCLUSIONS--Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme. Diabetes 59:311-318, 2010
ACCESSION #
47995281

 

Related Articles

  • Genetic find Functional Analyses of Melanocortin-4 Receptor Variants in Chinese Subjects. Fang, Qichen; Jia, Weiping; Zhang, Rong; Wang, Congrong; Hu, Cheng; Shao, Xinyu; Xiang, Kunsan // Diabetes;Jun2007 Supplement 1, Vol. 56, pA465 

    In the previous study, we had identified four variants in the melanocortin-4 receptor (MC4R) gene in Chinese subjects. Three polymorphisms (nt-216C/T, nt-178A/C and V103I) were detected in both obese and non-obese subjects and one missense mutation (F261S) was found in an early-onset obesity...

  • Bulk Segregation Mapping of Mutations in Closely Related Strains of Mice.  // Genetics;Dec2010, Vol. 186 Issue 4, p1139 

    No abstract available.

  • Obesity-programmed mice are rescued by early genetic intervention. Bumaschny, Viviana F.; Yamashita, Miho; Casas-Cordero, Rodrigo; Otero-Corchón, Verónica; de Souza, Flavio S. J.; Rubinstein, Marcelo; Low, Malcolm J. // Journal of Clinical Investigation;Nov2012, Vol. 122 Issue 11, p4203 

    Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in manag-ing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight...

  • Insertion/deletion coding polymorphisms in hHAVcr-1 are not associated with atopic asthma in the Japanese population. Noguchi, E; Nakayama, J; Kamioka, M; Ichikawa, K; Shibasaki, M; Arinami, T // Genes & Immunity;Mar2003, Vol. 4 Issue 2, p170 

    Hepatitis A virus receptor (HAVcr-1) and T-ceil immunoglobulin- and mucin-domain-containing molecule (TIM)-3 were recently implicated as asthma susceptibility genes in the study of congenic mice. In a genome-wide screen, we found strong evidence for linkage of atopic asthma with marker D5S820,...

  • Chronic Adolescent Exposure to Delta-9-Tetrahydrocannabinol in COMT Mutant Mice: Impact on Indices of Dopaminergic, Endocannabinoid and GABAergic Pathways. Behan, Áine T; Hryniewiecka, Magdalena; O'Tuathaigh, Colm M P; Kinsella, Anthony; Cannon, Mary; Karayiorgou, Maria; Gogos, Joseph A; Waddington, John L; Cotter, David R // Neuropsychopharmacology;Jun2012, Vol. 37 Issue 7, p1773 

    Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent...

  • Development of Obesity is Associated with Increased Calories per Meal Rather than per Day. A Study of High-Fat Diet-Induced Obesity in Young Rats. Furnes, Marianne W.; Chun-Mei Zhao; Duan Chen // Obesity Surgery;Oct2009, Vol. 19 Issue 10, p1430 

    The article discusses a study that challenged the current belief that obesity is a result of overnutrition by examining a rodent model of human obesity. Results revealed that the young rats on high fat diet even before becoming overweight consumed larger portions of meals and ate faster but less...

  • Modeling Neuropsychiatric Disease-Relevant Human SNPs in Mice. Blendy, Julie A. // Neuropsychopharmacology;Jan2011, Vol. 36 Issue 1, p364 

    The article cites a research study that analyzes single nucleotide polymorphisms (SNPs) in mice to understand how humans respond to disease, environment, and drugs. SNPs are variations in DNA sequence with an altered single nucleotide in the genome. The analysis of varied aspects of gene...

  • Identification of a Loss-of-Function Mutation in Ube216 Associated With Obesity Resistance. Marcelin, Genevieve; Shun-Mei Liu; Schwartz, Gary J.; Chua Jr., Streamson C. // Diabetes;Aug2013, Vol. 62 Issue 8, p2784 

    We previously mapped a locus on BALB/c chromosome 2 associated with protection from leptin-deficiency-induced obesity. Here, we generated the corresponding congenic mouse strain by introgression of a segment of C57BL/6J chromosome 2 to the BALB/c background to confirm the genotype-phenotype...

  • Absence of leptin deficiency mutation in extremely obese German children and adolescents. Hinney, A; Bornscheuer, A; Depenbusch, M; Mierke, B; Tölle, A; Mayer, H; Siegfried, W; Remschmidt, H; Hebebrand, J // International Journal of Obesity & Related Metabolic Disorders;Dec1997, Vol. 21 Issue 12, p1190 

    Comments on the absence of leptin deficiency mutations in extremely obese children and adolescents in Germany. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on the study of obesity.

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics