Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans
Erik Schoenmakers, … , Mark Gurnell, Krishna Chatterjee
Erik Schoenmakers, … , Mark Gurnell, Krishna Chatterjee
Published November 15, 2010
Citation Information: J Clin Invest. 2010;120(12):4220-4235. https://doi.org/10.1172/JCI43653.
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Research Article Genetics

Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans

Abstract

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence–binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation–induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Authors

Erik Schoenmakers, Maura Agostini, Catherine Mitchell, Nadia Schoenmakers, Laura Papp, Odelia Rajanayagam, Raja Padidela, Lourdes Ceron-Gutierrez, Rainer Doffinger, Claudia Prevosto, Jian’an Luan, Sergio Montano, Jun Lu, Mireille Castanet, Nick Clemons, Matthijs Groeneveld, Perrine Castets, Mahsa Karbaschi, Sri Aitken, Adrian Dixon, Jane Williams, Irene Campi, Margaret Blount, Hannah Burton, Francesco Muntoni, Dominic O’Donovan, Andrew Dean, Anne Warren, Charlotte Brierley, David Baguley, Pascale Guicheney, Rebecca Fitzgerald, Alasdair Coles, Hill Gaston, Pamela Todd, Arne Holmgren, Kum Kum Khanna, Marcus Cooke, Robert Semple, David Halsall, Nicholas Wareham, John Schwabe, Lucia Grasso, Paolo Beck-Peccoz, Arthur Ogunko, Mehul Dattani, Mark Gurnell, Krishna Chatterjee

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Figure 6

Impaired antioxidant defence in dermal fibroblasts.

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Altered expression of selenoproteome members in P1 and P2. (A) Relative ...
Endogenous H2O2 production by fibroblasts from P1 (A) and P2 (F) and age- and sex-matched controls was assayed using a specific indicator, as described in Methods. ROS levels in fibroblasts from P1 (B) and P2 (G) and age- and sex-matched controls were determined by loading cells with APF at intervals (1–60 minutes) following H2O2 exposure (0.5 mM, 30 minutes), with measurement of fluorescence by FACS analysis. (Fluorescence in the absence of APF was set arbitrarily at 1.) DNA damage, determined using an alkaline comet assay, was assessed in fibroblasts from P1 (C) and P2 (H) and age- and sex-matched controls in the absence and presence of exogenous H2O2 (50 μM), with or without addition of hOGG1, which targets oxidatively modified DNA (8-oxoGua) for excision (see Methods). Fluorescence microscopy images (original magnification, ×63) showing 8-oxoGua levels in fibroblasts from P1 (D) and P2 (I) and matched controls either untreated or exposed to H2O2 (50 μM), with DAPI staining and overlay confirming its nuclear localization, and γH2AX foci in fibroblasts from P1 (E) and P2 (J) and matched controls, either untreated or exposed to H2O2 (100 μM), with DAPI staining and overlay.