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Mutations in SECISBP2 result in abnormal thyroid hormone metabolism

Nature Genetics volume 37, pages 1247–1252 (2005)Cite this article

Abstract

Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNASec die in utero1, 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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Figure 1: Selenoprotein synthesis, the feedback regulation of thyroid hormone synthesis and secretion, and its metabolism.
Figure 2: TFTs for family members and the effect of L-T4 and L-T3 on TSH suppression.
Figure 3: DIO2 enzymatic activity and mRNA expression in fibroblasts from two affected children (individuals III-2 and III-6 from family A, shown in duplicate) and six unaffected individuals (siblings III-3 and III-5 and mother and maternal uncle from family A and two unrelated normal individuals, shown as average results per individual from four independent experiments).
Figure 4: Linkage analysis of candidate genes and identification of SECISBP2 mutations.
Figure 5: TFTs for family members and identification of SECISBP2 mutations.
Figure 6: Effect of SBP2 defect on other selenoproteins and serum Se concentrations.

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Acknowledgements

We thank N.H. Scherberg and his laboratory staff for doing the tests of thyroid function in sera; all members of the families for their willingness to participate in this study; I. Abo Alnoor and A. Abomelha for their help and support; H. Hoey and M. Adress for referral of the proband of family B; M.-S. McPeek and U. Schweizer for advice; A. Hernandez and D. St. Germain for their efforts to measure DIO3 enzymatic activity in fibroblasts; J. Köhrle for his advice and help with selenoprotein analysis; K.J. Millen, G.I. Bell and D.F. Steiner for critical reading of the manuscript; F.E. Wondisford for contributing to Figure 1; and V.A. Galton for sharing with us unpublished data on the mice with combined Dio1 and Dio2 targeted disruption and for allowing us to mention these data as personal communication. This work was supported in part by grants from the US National Institutes of Health and from the Deutsche Forschungsgemeinschaft. A.M.D. is a Howard Hughes Medical Institute Predoctoral Fellow.

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Author notes

  1. Joaquin Lado-Abeal

    Present address: Department of Medicine, University of Santiago de Compostela, Spain

Authors and Affiliations

  1. Department of Human Genetics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Alexandra M Dumitrescu

  2. Department of Medicine, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Xiao-Hui Liao, Joaquin Lado-Abeal, Lars C Moeller, Roy E Weiss & Samuel Refetoff

  3. Pediatric Endocrinology, Security Forces Hospital, Riyadh, Saudi Arabia

    Mohamed S Y Abdullah

  4. Prince Abdullah Hospital, Bisha, Saudi Arabia

    Fathia Abdul Majed

  5. Department of Pathology, Adelaide and Meath Hospital, Dublin, Ireland

    Gerard Boran

  6. Institute of Experimental Endocrinology, Charité Universitätsmedizin, Berlin, Germany

    Lutz Schomburg

  7. Department of Pediatrics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Samuel Refetoff

  8. Committee on Genetics, University of Chicago, MC 3090, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Samuel Refetoff

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Correspondence to Samuel Refetoff.

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Dumitrescu, A., Liao, XH., Abdullah, M. et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 37, 1247–1252 (2005). https://doi.org/10.1038/ng1654

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