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

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

doi:10.1016/j.ajhg.2009.06.002

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

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

Research output: Contribution to journal › Article › peer-review

Abstract

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 senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.

Original language	English
Pages (from-to)	106-111
Number of pages	6
Journal	American Journal of Human Genetics
Volume	85
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2009.06.002
State	Published - 10 Jul 2009
Externally published	Yes

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10.1016/j.ajhg.2009.06.002

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Boissel, S., Reish, O., Proulx, K., Kawagoe-Takaki, H., Sedgwick, B., Yeo, G. S. H., Meyre, D., Golzio, C., Molinari, F., Kadhom, N., Etchevers, H. C., Saudek, V., Farooqi, I. S., Froguel, P., Lindahl, T., O'Rahilly, S., Munnich, A., & Colleaux, L. (2009). Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations. American Journal of Human Genetics, 85(1), 106-111. https://doi.org/10.1016/j.ajhg.2009.06.002

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, Vladimir ; Farooqi, I. Sadaf ; Froguel, Philippe ; Lindahl, Tomas ; O'Rahilly, Stephen ; Munnich, Arnold ; Colleaux, Laurence. / Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations. In: American Journal of Human Genetics. 2009 ; Vol. 85, No. 1. pp. 106-111.

@article{a64e7b8d5de24ef091298fec7c0f2a2e,

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

abstract = "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 senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.",

author = "Sarah Boissel and Orit Reish and Karine Proulx and Hiroko Kawagoe-Takaki and Barbara Sedgwick and Yeo, {Giles S.H.} and David Meyre and Christelle Golzio and Florence Molinari and Noman Kadhom and Etchevers, {Heather C.} and Vladimir Saudek and Farooqi, {I. Sadaf} and Philippe Froguel and Tomas Lindahl and Stephen O'Rahilly and Arnold Munnich and Laurence Colleaux",

note = "Funding Information: We are grateful to the patients for their participation in the study. We acknowledge Jean Philippe Jais for LOD score calculation, Carron Sher for participation to clinical evaluation, Uli R{\"u}ther for kindly providing FTO antibodies, C{\'e}line Cluzeau for help with western blotting, Peter Robins for purification of FTO protein, and Marcella Ma and Debbie Lyon for additional technical assistance. This study was supported by the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche, the R{\'e}gion Ile-de-France, EU FP6 EUGENE2 (LSHM-CT-2004-512013), EC FP6 Marie Curie, the Medical Research Council UK, Cancer Research UK, the Wellcome Trust, and NIHR Cambridge Biomedical Research Centre. ",

year = "2009",

month = jul,

day = "10",

doi = "10.1016/j.ajhg.2009.06.002",

language = "אנגלית",

volume = "85",

pages = "106--111",

journal = "American Journal of Human Genetics",

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Boissel, S, Reish, O, Proulx, K, Kawagoe-Takaki, H, Sedgwick, B, Yeo, GSH, Meyre, D, Golzio, C, Molinari, F, Kadhom, N, Etchevers, HC, Saudek, V, Farooqi, IS, Froguel, P, Lindahl, T, O'Rahilly, S, Munnich, A & Colleaux, L 2009, 'Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations', American Journal of Human Genetics, vol. 85, no. 1, pp. 106-111. https://doi.org/10.1016/j.ajhg.2009.06.002

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, Vladimir; Farooqi, I. Sadaf; Froguel, Philippe; Lindahl, Tomas; O'Rahilly, Stephen; Munnich, Arnold; Colleaux, Laurence.

In: American Journal of Human Genetics, Vol. 85, No. 1, 10.07.2009, p. 106-111.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Loss-of-Function Mutation in the Dioxygenase-Encoding FTO Gene Causes Severe Growth Retardation and Multiple Malformations

AU - Boissel, Sarah

AU - Reish, Orit

AU - Proulx, Karine

AU - Kawagoe-Takaki, Hiroko

AU - Sedgwick, Barbara

AU - Yeo, Giles S.H.

AU - Meyre, David

AU - Golzio, Christelle

AU - Molinari, Florence

AU - Kadhom, Noman

AU - Etchevers, Heather C.

AU - Saudek, Vladimir

AU - Farooqi, I. Sadaf

AU - Froguel, Philippe

AU - Lindahl, Tomas

AU - O'Rahilly, Stephen

AU - Munnich, Arnold

AU - Colleaux, Laurence

N1 - Funding Information: We are grateful to the patients for their participation in the study. We acknowledge Jean Philippe Jais for LOD score calculation, Carron Sher for participation to clinical evaluation, Uli Rüther for kindly providing FTO antibodies, Céline Cluzeau for help with western blotting, Peter Robins for purification of FTO protein, and Marcella Ma and Debbie Lyon for additional technical assistance. This study was supported by the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche, the Région Ile-de-France, EU FP6 EUGENE2 (LSHM-CT-2004-512013), EC FP6 Marie Curie, the Medical Research Council UK, Cancer Research UK, the Wellcome Trust, and NIHR Cambridge Biomedical Research Centre.

PY - 2009/7/10

Y1 - 2009/7/10

N2 - 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 senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.

AB - 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 senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.

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ER -

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

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