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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.

SUBMITTER: Schoenmakers E 

PROVIDER: S-EPMC2993594 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

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

The Journal of clinical investigation 20101115 12


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 p  ...[more]

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