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

被引：228

作者：

Schoenmakers, Erik ^{[1
]}

Agostini, Maura ^{[1
]}

Mitchell, Catherine ^{[1
]}

Schoenmakers, Nadia ^{[1
]}

Papp, Laura ^{[2
]}

Rajanayagam, Odelia ^{[1
]}

Padidela, Raja ^{[3
]}

Ceron-Gutierrez, Lourdes ^{[4
]}

Doffinger, Rainer ^{[4
]}

Prevosto, Claudia ^{[5
]}

Luan, Jian'an ^{[6
]}

Montano, Sergio ^{[7
]}

Lu, Jun ^{[7
]}

Castanet, Mireille ^{[1
]}

Clemons, Nick ^{[8
]}

Groeneveld, Matthijs

Castets, Perrine ^{[9
]}

Karbaschi, Mahsa ^{[10
,11
]}

Aitken, Sri ^{[12
]}

Dixon, Adrian ^{[12
]}

Williams, Jane

Campi, Irene ^{[1
]}

Blount, Margaret ^{[1
]}

Burton, Hannah ^{[1
]}

Muntoni, Francesco ^{[13
]}

O'Donovan, Dominic ^{[14
]}

Dean, Andrew ^{[14
]}

Warren, Anne ^{[14
]}

Brierley, Charlotte ^{[15
]}

Baguley, David ^{[16
]}

Guicheney, Pascale ^{[9
]}

Fitzgerald, Rebecca ^{[8
]}

Coles, Alasdair ^{[17
]}

Gaston, Hill ^{[5
]}

Todd, Pamela ^{[18
]}

Holmgren, Arne ^{[7
]}

Khanna, Kum Kum ^{[2
]}

Cooke, Marcus ^{[10
,11
]}

Semple, Robert ^{[1
]}

Halsall, David ^{[19
]}

Wareham, Nicholas ^{[6
]}

Schwabe, John ^{[20
]}

Grasso, Lucia ^{[21
]}

Beck-Peccoz, Paolo ^{[22
]}

Ogunko, Arthur ^{[23
]}

Dattani, Mehul ^{[3
]}

Gurnell, Mark ^{[1
,5
]}

Chatterjee, Krishna ^{[1
,5
]}

机构：

[1] Univ Cambridge, Inst Metab Sci, Cambridge CB2 0QQ, England

[2] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[3] Great Ormond St Hosp Sick Children, London WC1N 3JH, England

[4] Univ Cambridge, Dept Clin Immunol, Cambridge CB2 0QQ, England

[5] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England

[6] MRC Epidemiol Unit, Cambridge, England

[7] Karolinska Inst, Med Nobel Inst Biochem, Stockholm, Sweden

[8] MRC Canc Cell Unit, Cambridge, England

[9] Hop La Pitie Salpetriere, INSERM, UMR S956, Paris, France

[10] Univ Leicester, Dept Mol Med, Dept Canc Studies, Leicester, Leics, England

[11] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[12] Univ Cambridge, Dept Radiol, Cambridge CB2 0QQ, England

[13] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London, England

[14] Univ Cambridge, Dept Histopathol, Cambridge CB2 0QQ, England

[15] Univ Cambridge, Dept Neurol, Cambridge CB2 0QQ, England

[16] Univ Cambridge, Dept Audiol, Cambridge CB2 0QQ, England

[17] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England

[18] Univ Cambridge, Dept Dermatol, Cambridge CB2 0QQ, England

[19] Univ Cambridge, Dept Clin Biochem, Cambridge CB2 0QQ, England

[20] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England

[21] Univ Pisa, Dept Endocrinol, Pisa, Italy

[22] Fdn Policlin IRCCS, Dept Med Sci, Milan, Italy

[23] Darent Valley Hosp, Dartford, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2010年 / 120卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

SELENIUM SUPPLEMENTATION; SULFOXIDE-REDUCTASE; MUSCULAR-DYSTROPHY; OXIDATIVE STRESS; HEARING-LOSS; MICE; THIOREDOXIN; EXPRESSION; SBP2; TRANSLATION;

D O I：

10.1172/JCI43653

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

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.

引用

页码：4220 / 4235

页数：16

共 72 条

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