Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations

Boissel, Sarah; Reish, Orit; Proulx, Karine; Kawagoe-Takaki, Hiroko; Sedgwick, Barbara; Yeo, Giles S.H.; Meyre, David; Golzio, Christelle; Molinari, Florence; Kadhom, Noman; Etchevers, Heather C.; Saudek, Vladimı́r; Farooqi, I. Sadaf; Froguel, Philippe; Lindahl, Tomas; O’Rahilly, Stephen; Münnich, Arnold; Colleaux, Laurence

doi:10.1016/j.ajhg.2009.06.002

Cited by 349 publications

(346 citation statements)

References 25 publications

Supporting

Mentioning

327

Contrasting

Unclassified

Order By: Relevance

“…This knockout therefore did not test the function of the risk LD block, nor do these results contradict our findings. A second publication reported human FTO to be a gene causing recessive multiple malformations and lethality in early childhood, also accompanied by growth retardation (36). Interestingly, the authors noted the absence of obesity in the heterozygous parents.…”

Section: Discussionmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

152

View full text Add to dashboard Cite

Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes

show abstract

Section: Discussionmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

152

View full text Add to dashboard Cite

show abstract

“…One of the most striking features of mice lacking FTO (10), or humans homozygous for an enzymatically inactive mutated FTO (11), is severe growth retardation. We hypothesized that exploring the mechanisms underlying this phenotype might provide clues to the physiological functions of FTO.…”

Section: Resultsmentioning

confidence: 99%

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Gulati

Cheung

Antrobus

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

158

147

View full text Add to dashboard Cite

SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.genetics | translation | tRNA synthetase | demethylase I n 2007, single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity related (FTO) were found to be powerfully associated with body mass index and predisposing to childhood and adult obesity (1). Many subsequent studies, covering multiple populations of European, African, and Asian ancestries, across different age ranges, have confirmed the association of FTO with body mass index (reviewed in ref.2). It is clear from the weight of evidence that the major effect of SNPs in FTO is on increased energy intake, with reduction in satiety (3-8). To date, no conclusive link has been made between the risk alleles and expression or function of FTO. However, transgenic manipulation in mice supports the notion that FTO itself regulates body weight, with overexpression resulting in obesity (9), whereas Fto-null mice (10) and humans homozygous for a loss-of-function allele (11) display postnatal growth retardation and have high rates of early mortality.FTO is widely expressed across multiple tissues, although it is most highly expressed in the brain, especially in the hypothalamus, a region that plays a key role in the control of energy homeostasis (12). We have found that expression of FTO, specifically in the arcuate nucleus of the hypothalamus, is bidirectionally regulated as a function of nutritional status-decreasing following a 48-h fast and increasing after 10 wk of exposure to a high-fat diet-and that modulating FTO levels specifically in the arcuate nucleus can influence food intake (13). Carriers of the obesity predisposing allele are hyperphagic and show altered macronutrient preference.FTO shares sequence motifs with Fe(II)-and 2-oxoglutaratedependent oxygenases (12). In vitro, recombinant FTO is able to catalyze the Fe(II)-and 2-oxoglutarate-dependent demethylation of nucleic acids. It is more active at RNA than DNA (12,14) and is capable of demethylating N6-methyladenosine (15) (more prevalent on mRNAs) or 3-methyluracil (15) (more prevalent in tRNAs and ribosomal RNAs). To date, however, there has been no understanding of how FTO might functionally link to energy homeostasis, growth, or nutrient sensing. ResultsOne of the most striking features of mice lacking FTO (10), or humans homozygous for an enzymatically inactive mutated FTO (11), is severe growth ...

show abstract

“…5 This hypothesis is supported by the clinical findings in rare patients and in mouse models with an FTO/Fto mutation. Homozygous loss-of-function of FTO was reported to cause severe growth retardation and multiple malformations, 6 whereas a duplication of FTO was found to be associated with morbid obesity. 7 Fto-knockout mice 8 and mice with a missense mutation in exon 6 9 showed leanness, postnatal growth retardation and a higher metabolic rate.…”

Section: Introductionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

View full text Add to dashboard Cite

A block of single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity associated) gene is associated with variation in body weight. Previous works suggest that increased expression of FTO, which encodes a 2-oxoglutaratedependent nucleic acid demethylase, leads to increased body weight, although the underlying mechanism has remained unclear. To elucidate the function of FTO, we examined the consequences of altered FTO levels in cultured cells and murine brain. Here we show that a knockdown of FTO in HEK293 cells affects the transcripts levels of genes involved in the response to starvation, whereas overexpression of FTO affects the transcript levels of genes related to RNA processing and metabolism. Subcellular localization of FTO further strengthens the latter notion. Using immunocytochemistry and confocal laser scanning microscopy, we detected FTO in nuclear speckles and -to a lesser and varying extent -in the nucleoplasm and nucleoli of HEK293, HeLa and MCF-7 cells. Moreover, RNA modification analyses revealed that loss of Fto affects the 3-methyluridine/ uridine and pseudouridine/uridine ratios in total brain RNA. We conclude that altered levels of FTO have multiple and diverse consequences on RNA modifications and the transcriptome. Keywords: FTO; RNA modifications; nuclear speckles; transcriptome INTRODUCTION Genome-wide association studies have revealed a strong association between a block of single-nucleotide polymorphisms (SNPs) in intron 1 of the fat mass and obesity-associated (FTO) gene, body mass index and other obesity-related traits in children and adults of different populations. 1-3 Stratigopoulos et al 4 have suggested that one of the SNPs (rs8050136) affects binding of the transcriptional regulator CUX1. By studying allelic expression levels in heterozygous individuals, we have found that the risk allele of the FTO gene makes more transcripts and have proposed that increased expression of the FTO gene leads to increased body weight. 5 This hypothesis is supported by the clinical findings in rare patients and in mouse models with an FTO/Fto mutation. Homozygous loss-of-function of FTO was reported to cause severe growth retardation and multiple malformations, 6 whereas a duplication of FTO was found to be associated with morbid obesity. 7 Fto-knockout mice 8 and mice with a missense mutation in exon 6 9 showed leanness, postnatal growth retardation and a higher metabolic rate. Mice with one or two additional copies of Fto had a gene-dosage-dependent increase in body weight. 10 FTO is a member of non-heme Fe(II)-and a-ketoglutaratedependent oxygenase superfamily and is found in vertebrates and green algea, but not in invertebrate animals, fungi and green plants. 11 By in vitro studies, FTO was shown to function as a demethylase with a strong preference for 3meU and 3meT in single-stranded RNA and DNA, respectively. 12,13 Han et al 14 have provided structural evidence for understanding the substrate specificity of FTO and have suggested

show abstract

Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations

Cited by 349 publications

References 25 publications

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Role for the obesity-related FTO gene in the cellular sensing of amino acids

FTO levels affect RNA modification and the transcriptome

Contact Info

Product

Resources

About