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

被引：401

作者：

Boissel, Sarah ^{[1
,2
]}

Reish, Orit ^{[3
,4
]}

Proulx, Karine ^{[5
]}

Kawagoe-Takaki, Hiroko ^{[6
]}

Sedgwick, Barbara ^{[6
]}

Yeo, Giles S. H. ^{[5
]}

Meyre, David ^{[7
]}

Golzio, Christelle ^{[1
,2
]}

Molinari, Florence ^{[1
,2
]}

Kadhom, Noman ^{[1
,2
]}

Etchevers, Heather C. ^{[1
,2
]}

Saudek, Vladimir ^{[5
]}

Farooqi, I. Sadaf ^{[5
]}

Froguel, Philippe ^{[7
,8
]}

Lindahl, Tomas ^{[6
]}

O'Rahilly, Stephen ^{[5
]}

Munnich, Arnold ^{[1
,2
]}

Colleaux, Laurence ^{[1
,2
]}

机构：

[1] Univ Paris 05, Hop Necker Enfants Malad, INSERM, U781, F-75015 Paris, France

[2] Univ Paris 05, Hop Necker Enfants Malad, Dept Genet, F-75015 Paris, France

[3] Assaf Harofeh Med Ctr, Dept Med Genet, IL-70300 Zerifin, Israel

[4] Tel Aviv Univ, Sackler Sch Med, IL-70300 Zerifin, Israel

[5] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England

[6] Imperial Canc Res Fund, Clare Hall Labs, Canc Res UK London Res Inst, S Mimms EN6 3LD, Herts, England

[7] Inst Pasteur, CNRS, Inst Biol 8090, F-59019 Lille, France

[8] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sect Genom Med, London W12 0NN, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2009年 / 85卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

OXIDATIVE DEMETHYLATION; ENERGY-EXPENDITURE; ALKYLATION DAMAGE; ESCHERICHIA-COLI; ADULT OBESITY; FUSED-TOES; DNA; ALKB; MOUSE; MICE;

D O I：

10.1016/j.ajhg.2009.06.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 polymal formation syndrome.

引用

页码：106 / 111

页数：6

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