Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.

@article{Boissel2009LossoffunctionMI,
  title={Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.},
  author={S. Boissel and O. Reish and K. Proulx and Hiroko Kawagoe-Takaki and B. Sedgwick and G. Yeo and D. Meyre and C. Golzio and F. Molinari and N. Kadhom and H. Etchevers and V. Saudek and I. Farooqi and P. Froguel and T. Lindahl and S. O’Rahilly and A. Munnich and L. Colleaux},
  journal={American journal of human genetics},
  year={2009},
  volume={85 1},
  pages={
          106-11
        }
}
FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. Although polymorphisms within the first intron of the FTO gene have been associated with obesity, the physiological role of FTO remains unknown. Here we show that a R316Q mutation, inactivating FTO enzymatic activity, is responsible for an autosomal-recessive lethal syndrome. Cultured skin fibroblasts from affected subjects showed impaired proliferation and accelerated… Expand
Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay
TLDR
The findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems. Expand
A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP
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A patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities is described. Expand
Role for the obesity-related FTO gene in the cellular sensing of amino acids
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A role for FTO is described in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling, suggesting that FTO may influence body composition through playing a role in cellular nutrient sensing. Expand
The biology of FTO: from nucleic acid demethylase to amino acid sensor
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In vivo and in vitro evidence detailing the complex biology of FTO is explored and how these might link to the regulation of body weight is discussed. Expand
Pharmacological Inhibition of FTO
TLDR
It was shown that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro, however, FTO protein levels were not significantly altered by treatment of mice with IOx3 at 60 mg/kg every two days. Expand
Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.
  • S. Ghosh, Sangmoon Lee, +27 authors J. Gleeson
  • Medicine, Biology
  • Genetics in medicine : official journal of the American College of Medical Genetics
  • 2020
TLDR
The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition. Expand
Hypomorphism of Fto and Rpgrip1l causes obesity in mice.
TLDR
The results of this study indicate that the effects of FTO-associated SNPs on energy homeostasis are due in part to the results of these genetic variations on hypothalamic FTO, RPGRIP1L, and possibly other genes. Expand
FTO demethylase activity is essential for normal bone growth and bone mineralization in mice
TLDR
It is demonstrated that FTO catalytic activity is not required fornormal body composition although it is required for normal body size and viability, and it is also essential for normal bone growth and mineralization, a previously unreported FTO function. Expand
Loss of FTO Antagonises Wnt Signaling and Leads to Developmental Defects Associated with Ciliopathies
TLDR
It is demonstrated that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish, the first evidence that FTO plays a role in development and cilia formation/function. Expand
FTO variant associated with malformation syndrome
TLDR
The phenotype of homozygous FTO loss‐of‐function mutations is expanded to include eye abnormalities, gingival overgrowth, craniosynostosis, and cutaneous photosensitivity. Expand
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Inactivation of the Fto gene protects from obesity
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These experiments provide the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure, and leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. Expand
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It is found that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Expand
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A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity
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A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). Expand
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