• PMID: 21084748
• Gene Name: SECISBP2
• Condition: Azoospermia
• Association: Associated
• Sex: Male
• Infertility type: Male infertility

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

Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K.

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. FAU - Schoenmakers, Erik AU - Schoenmakers E AD - Institute of Metabolic Science, University of Cambridge, Cambridge, UK. FAU - Agostini, Maura AU - Agostini M FAU - Mitchell, Catherine AU - Mitchell C FAU - Schoenmakers, Nadia AU - Schoenmakers N FAU - Papp, Laura AU - Papp L FAU - Rajanayagam, Odelia AU - Rajanayagam O FAU - Padidela, Raja AU - Padidela R FAU - Ceron-Gutierrez, Lourdes AU - Ceron-Gutierrez L FAU - Doffinger, Rainer AU - Doffinger R FAU - Prevosto, Claudia AU - Prevosto C FAU - Luan, Jian'an AU - Luan J FAU - Montano, Sergio AU - Montano S FAU - Lu, Jun AU - Lu J FAU - Castanet, Mireille AU - Castanet M FAU - Clemons, Nick AU - Clemons N FAU - Groeneveld, Matthijs AU - Groeneveld M FAU - Castets, Perrine AU - Castets P FAU - Karbaschi, Mahsa AU - Karbaschi M FAU - Aitken, Sri AU - Aitken S FAU - Dixon, Adrian AU - Dixon A FAU - Williams, Jane AU - Williams J FAU - Campi, Irene AU - Campi I FAU - Blount, Margaret AU - Blount M FAU - Burton, Hannah AU - Burton H FAU - Muntoni, Francesco AU - Muntoni F FAU - O'Donovan, Dominic AU - O'Donovan D FAU - Dean, Andrew AU - Dean A FAU - Warren, Anne AU - Warren A FAU - Brierley, Charlotte AU - Brierley C FAU - Baguley, David AU - Baguley D FAU - Guicheney, Pascale AU - Guicheney P FAU - Fitzgerald, Rebecca AU - Fitzgerald R FAU - Coles, Alasdair AU - Coles A FAU - Gaston, Hill AU - Gaston H FAU - Todd, Pamela AU - Todd P FAU - Holmgren, Arne AU - Holmgren A FAU - Khanna, Kum Kum AU - Khanna KK FAU - Cooke, Marcus AU - Cooke M FAU - Semple, Robert AU - Semple R FAU - Halsall, David AU - Halsall D FAU - Wareham, Nicholas AU - Wareham N FAU - Schwabe, John AU - Schwabe J FAU - Grasso, Lucia AU - Grasso L FAU - Beck-Peccoz, Paolo AU - Beck-Peccoz P FAU - Ogunko, Arthur AU - Ogunko A FAU - Dattani, Mehul AU - Dattani M FAU - Gurnell, Mark AU - Gurnell M