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

Schoenmakers, Erik, Agostini, Maura, Mitchell, Catherine, Schoenmakers, Nadia, Papp, Laura, Rajanayagam, Odelia, Padidela, Raja, Ceron-Gutierrez, Lourdes, Doffinger, Rainer, Prevosto, Claudia, Luan, Jian'an, Montano, Sergio, Lu, Jun, Castanet, Mireille, Clemons, Nick, Groeneveld, Matthijs, Castets, Perrine, Karbaschi, Mahsa, Aitken, Sri, Dixon, Adrian, Williams, Jane, Campi, Irene, Blount, Margaret, Burton, Hannah, Muntoni, Francesco, O'Donovan, Dominic, Dean, Andrew, Warren, Anne, Brierley, Charlotte, Baguley, David, Guicheney, Pascale, Fitzgerald, Rebecca, Coles, Alasdair, Gaston, Hill, Todd, Pamela, Holmgren, Arne, Khanna, Kum Kum, Cooke, Marcus, Semple, Robert, Halsall, David, Wareham, Nicholas, Schwabe, John, Grasso, Lucia, Beck-Peccoz, Paolo, Ogunko, Arthur, Dattani, Mehul, Gurnell, Mark and Chatterjee, Krishna (2010) Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. Journal of Clinical Investigation, 120 12: 4220-4235. doi:10.1172/JCI43653

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Author Schoenmakers, Erik
Agostini, Maura
Mitchell, Catherine
Schoenmakers, Nadia
Papp, Laura
Rajanayagam, Odelia
Padidela, Raja
Ceron-Gutierrez, Lourdes
Doffinger, Rainer
Prevosto, Claudia
Luan, Jian'an
Montano, Sergio
Lu, Jun
Castanet, Mireille
Clemons, Nick
Groeneveld, Matthijs
Castets, Perrine
Karbaschi, Mahsa
Aitken, Sri
Dixon, Adrian
Williams, Jane
Campi, Irene
Blount, Margaret
Burton, Hannah
Muntoni, Francesco
O'Donovan, Dominic
Dean, Andrew
Warren, Anne
Brierley, Charlotte
Baguley, David
Guicheney, Pascale
Fitzgerald, Rebecca
Coles, Alasdair
Gaston, Hill
Todd, Pamela
Holmgren, Arne
Khanna, Kum Kum
Cooke, Marcus
Semple, Robert
Halsall, David
Wareham, Nicholas
Schwabe, John
Grasso, Lucia
Beck-Peccoz, Paolo
Ogunko, Arthur
Dattani, Mehul
Gurnell, Mark
Chatterjee, Krishna
Title Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
Publication date 2010-12
Sub-type Article (original research)
DOI 10.1172/JCI43653
Open Access Status DOI
Volume 120
Issue 12
Start page 4220
End page 4235
Total pages 16
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Collection year 2011
Language eng
Formatted abstract
Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as seleno-cysteine (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 photo-sensitivity. 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.
Keyword Mediated cell-death
Human skin
Oxidative stress
Hearing loss
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
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Created: Fri, 01 Apr 2011, 08:32:41 EST by Debbie Banks on behalf of School of Medicine