Nature Genetics 37, 1247 - 1252 (2005)
Published online: 16 October 2005; | doi:10.1038/ng1654
Mutations in SECISBP2 result in abnormal thyroid hormone metabolismAlexandra M Dumitrescu1, Xiao-Hui Liao2, Mohamed S Y Abdullah3, Joaquin Lado-Abeal2, 9, Fathia Abdul Majed4, Lars C Moeller2, Gerard Boran5, Lutz Schomburg6, Roy E Weiss2
& Samuel Refetoff2, 7, 81
Department of Human Genetics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, Illinois 60637, USA. 2
Department of Medicine, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, Illinois 60637, USA. 3
Pediatric Endocrinology, Security Forces Hospital, Riyadh, Saudi Arabia. 4
Prince Abdullah Hospital, Bisha, Saudi Arabia. 5
Department of Pathology, Adelaide and Meath Hospital, Dublin, Ireland. 6
Institute of Experimental Endocrinology, Charité Universitätsmedizin Berlin, Germany. 7
Department of Pediatrics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, Illinois 60637, USA. 8
Committee on Genetics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, Illinois 60637, USA. 9
Present address: Department of Medicine, University of Santiago de Compostela, Spain.
Correspondence should be addressed to Samuel Refetoff refetoff@uchicago.edu Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNASec die in utero
1, but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in thyroid hormone metabolism. We identified three of seven siblings with clinical evidence of abnormal thyroid hormone metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2. Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.
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