Investigation of a patient with a partial trisomy 16q including the fat mass and obesity associated gene (<i>FTO</i>): Fine mapping and <i>FTO</i> gene expression study

Berg, Linda Den Van; Waal, Henriette Delemarre Van De; Han, Joan C.; Ylstra, Bauke; Eijk, Paul P.; Nesterova, Maria; Heutink, Peter; Stratakis, Constantine A.

doi:10.1002/ajmg.a.33229

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

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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

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Section: Introductionmentioning

confidence: 99%

FTO levels affect RNA modification and the transcriptome

et al. 2012

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“…Similarly, in a recent report, a subject with an 11.45 Mb duplication on chromosome 16q, including the entire FTO locus, did not exhibit altered expression of FTO. 13 Although allele specific expression analysis of five individuals demonstrated that the obesity associated SNPs in intron 1 of FTO were associated with increased FTO expression in blood, 12 other studies revealed no effect of these SNPs on FTO expression in muscle or adipose tissues. 31 This suggest that the effects of common intronic SNPs in FTO on susceptibility to obesity may be mediated in part by altered expression of other genes in the region.…”

Section: Discussionmentioning

confidence: 98%

“…However, in subjects with proximal 16q duplications, including FTO, obesity is a common but not an inevitable feature in the background of significant psychomotor and intellectual deficits. 13 We therefore sought to determine whether rare copy-number variants (CNVs) (o1%) at the FTO locus are found in subjects at the extremes of the body weight distribution, and if so, to characterize the effect of those CNVs. We identified a single large CNV spanning the FTO risk locus and characterized its molecular effects, as well as the clinical features of the subject and affected family members.…”

Section: Introductionmentioning

confidence: 99%

A 680 kb duplication at the FTO locus in a kindred with obesity and a distinct body fat distribution

et al. 2013

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Common intronic SNPs in the human fat mass and obesity associated (FTO) gene are strongly associated with body mass index (BMI). In mouse models, inactivation of the Fto gene results in a lean phenotype, whereas overexpression of Fto leads to increased food intake and obesity. The latter finding suggests that copy number variants at the FTO locus might be associated with extremes of adiposity. To address this question, we searched for rare, private or de novo copy number variation in a cohort of 985 obese and 869 lean subjects of European ancestry drawn from the extremes of the BMI distribution, genotyped on Affymetrix 6.0 arrays. A B680 kb duplication, confirmed by real-time PCR and G-to-FISH analyses, was observed between Brs11859825 and rs9932411 in a 68-year-old male with severe obesity. The duplicated region on chromosome 16 spans the entire genome-wide association studies risk locus for obesity, and further encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene. Affected family members exhibit a unique obesity phenotype, characterized by increased fat distribution in the shoulders and neck with a significantly increased neck circumference. This phenotype was accompanied by increased peripheral blood expression of RBL2 with no alteration in expression of FTO or other genes in the region. No other duplications or deletions in this region were identified in the cohort of obese and lean individuals or in a further survey of 4778 individuals, suggesting that large rare copy number variants surrounding the FTO gene are not a frequent cause of obesity.

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“…Every chromosome except chromosome number 13 was found to be reported with structural anomalies (i.e., deletions, duplications) and related to obesity. These include chromosome 1 with a recognized 1p36 deletion obesity syndrome [45]; chromosome 6 with a 6q16.2 deletion involving SIM1 gene [46]; chromosome 11 with 11p deletions involving the BDNF gene [47]; chromosome 15 with the 15q11-q13 deletion seen in Prader-Willi syndrome [25]; chromosome 16 with 16p11.2 deletions involving the SH2B1 gene [25,26] and 16q11.2 duplications involving the FTO gene [48]; chromosome 18 with 18q deletions involving the MC4R gene [49]; chromosome 20 with 20q deletions seen in Albright hereditary osteodystrophy involving the complex GNAS1 gene locus [50]; chromosome 22 with the 22q11.2 deletion seen in DiGeorge syndrome [51]; and chromosome X with a Xq27 deletion involving the FMR1 gene seen in fragile X syndrome [52]. These multiple chromosome abnormalities support the polygenic nature of obesity useful for the identification of candidate genes and their location for more precise genetic characterization and testing.…”

Section: Yrbm Znf483mentioning

confidence: 99%

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

Butler

McGuire

Manzardo

2015

J Assist Reprod Genet

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Purpose Obesity is a growing public health concern now reaching epidemic status worldwide for children and adults due to multiple problems impacting on energy intake and expenditure with influences on human reproduction and infertility. A positive family history and genetic factors are known to play a role in obesity by influencing eating behavior, weight and level of physical activity and also contributing to human reproduction and infertility. Recent advances in genetic technology have led to discoveries of new susceptibility genes for obesity and causation of infertility. The goal of our study was to provide an update of clinically relevant candidate and known genes for obesity and infertility using high resolution chromosome ideograms with gene symbols and tabular form. Methods We used computer-based internet websites including PubMed to search for combinations of key words such as obesity, body mass index, infertility, reproduction, azoospermia, endometriosis, diminished ovarian reserve, estrogen along with genetics, gene mutations or variants to identify evidence for development of a master list of recognized obesity genes in humans and those involved with infertility and reproduction. Gene symbols for known and candidate genes for obesity were plotted on high resolution chromosome ideograms at the 850 band level. Both infertility and obesity genes were listed separately in alphabetical order in tabular form and those highlighted when involved with both conditions. Results By searching the medical literature and computer generated websites for key words, we found documented evidence for 370 genes playing a role in obesity and 153 genes for human reproduction or infertility. The obesity genes primarily affected common pathways in lipid metabolism, deposition or transport, eating behavior and food selection, physical activity or energy expenditure. Twenty-one of the obesity genes were also associated with human infertility and reproduction. Gene symbols were plotted on high resolution ideograms and their name, precise chromosome band location and description were summarized in tabular form. Conclusions Meaningful correlations in the obesity phenotype and associated human infertility and reproduction are represented with the location of genes on chromosome ideograms along with description of the gene and position in tabular form. These high resolution chromosome ideograms and tables will be useful in genetic awareness and counseling, diagnosis and treatment to improve clinical outcomes.

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Investigation of a patient with a partial trisomy 16q including the fat mass and obesity associated gene (FTO): Fine mapping and FTO gene expression study

Cited by 20 publications

References 34 publications

FTO levels affect RNA modification and the transcriptome

FTO levels affect RNA modification and the transcriptome

A 680 kb duplication at the FTO locus in a kindred with obesity and a distinct body fat distribution

Clinically relevant known and candidate genes for obesity and their overlap with human infertility and reproduction

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