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 1

Genotypes and biochemical phenotypes in 2 families with defects in SECISBP2.

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Genotypes and biochemical phenotypes in 2 families with defects in SECIS...
(A) Schematic representations of the coding exons of SECISBP2 (top) showing the location of aberrantly spliced variant transcripts (P1, green; P2, orange), and the major domains of SBP2 (bottom) showing the frameshift premature stop (P1, blue, fs255X) and missense (P2, red, C691R) mutations. NLS, nuclear localization signal; NES, nuclear export signal; L7Ae module, domain homolog to RNA-binding domain of L7Ae; M1, M233, M300, position of alternate methionine transcription initiation sites, with M1 yielding full-length wild-type SBP2 protein. (B and C) Pedigrees of families 1 (B) and 2 (C) showing genotypes (as described in A); squares and circles represent male and female family members, respectively, and arrows/filled symbols denote probands. Below, Western blotting for SEPP and GPx3 in plasma of both probands and family members. Black arrows indicate specific bands; white arrows denote nonspecific bands. Albumin was used as a loading control. (D) PBMCs from P1 and P2 demonstrate defective selenoprotein synthesis. Selenoprotein biosynthesis in PBMCs was assessed using 75Se labeling as described in Methods. 35S-Met labeling confirmed comparable protein loading. C, control subject (age- and sex-matched to P1). (E) Fibroblasts from P1 and P2 lack full-length SBP2. Whole cell lysates from primary skin fibroblasts were Western blotted for full-length (FL) SBP2 (arrow) with actin as a loading control. Age- and sex-matched control subjects were used.