Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.
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.
Boissel
Sarah
S
INSERM U781 and Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Reish
Orit
O
Proulx
Karine
K
Kawagoe-Takaki
Hiroko
H
Sedgwick
Barbara
B
Yeo
Giles S H
GS
Meyre
David
D
Golzio
Christelle
C
Molinari
Florence
F
Kadhom
Noman
N
Etchevers
Heather C
HC
Saudek
Vladimir
V
Farooqi
I Sadaf
IS
Froguel
Philippe
P
Lindahl
Tomas
T
O'Rahilly
Stephen
S
Munnich
Arnold
A
Colleaux
Laurence
L
D000015:Abnormalities, Multiple / Q000235:genetics*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000595:Amino Acid Sequence; D000818:Animals; D020022:Genetic Predisposition to Disease; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human