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

• Published in: American journal of human genetics Vol. 85; no. 1; pp. 106 - 111
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.07.2009; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Abnormalities, Multiple - genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Amino Acid Sequence; Animals; Biological and medical sciences; Cardiovascular system; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Growth Disorders - genetics; Human genetics; Humans; Life Sciences; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Obesity; Pedigree; Polymorphism; Proteins; Proteins - genetics; Sequence Alignment; Human; Loss function; Multiple; Gene; Malformation; Cause; Genetics; Mutation; Severe; Growth retardation
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2009.06.002

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.