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

• Published in: The Journal of clinical investigation Vol. 120; no. 12; pp. 4220 - 4235
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2010
• Subjects: Adult; Aged; Amino Acid Sequence; Animals; Azoospermia - genetics; Base Sequence; Binding proteins; Biomedical research; Child; Child, Preschool; Codon, Nonsense; DNA - genetics; DNA sequencing; Female; Gene mutations; Hearing Loss, Sensorineural - genetics; Humans; Identification and classification; Insulin Resistance - genetics; Male; Methods; Mice; Middle Aged; Models, Molecular; Molecular Sequence Data; Muscular Dystrophies - genetics; Mutation; Mutation, Missense; Nucleotide sequencing; Pedigree; Photosensitivity Disorders - genetics; Properties; Reactive Oxygen Species - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Selenocysteine; Selenocysteine - metabolism; Selenoproteins - deficiency; Selenoproteins - metabolism; Sequence Homology, Amino Acid; Spermatogenesis - genetics; T-Lymphocytes - immunology; United Kingdom
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI43653

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.