Document Detail

Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans.
MedLine Citation:
PMID:  21084748     Owner:  NLM     Status:  MEDLINE    
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.
Erik Schoenmakers; Maura Agostini; Catherine Mitchell; Nadia Schoenmakers; Laura Papp; Odelia Rajanayagam; Raja Padidela; Lourdes Ceron-Gutierrez; Rainer Doffinger; Claudia Prevosto; Jian'an Luan; Sergio Montano; Jun Lu; Mireille Castanet; Nick Clemons; Matthijs Groeneveld; Perrine Castets; Mahsa Karbaschi; Sri Aitken; Adrian Dixon; Jane Williams; Irene Campi; Margaret Blount; Hannah Burton; Francesco Muntoni; Dominic O'Donovan; Andrew Dean; Anne Warren; Charlotte Brierley; David Baguley; Pascale Guicheney; Rebecca Fitzgerald; Alasdair Coles; Hill Gaston; Pamela Todd; Arne Holmgren; Kum Kum Khanna; Marcus Cooke; Robert Semple; David Halsall; Nicholas Wareham; John Schwabe; Lucia Grasso; Paolo Beck-Peccoz; Arthur Ogunko; Mehul Dattani; Mark Gurnell; Krishna Chatterjee
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-15
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-02     Completed Date:  2011-01-14     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4220-35     Citation Subset:  AIM; IM    
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MeSH Terms
Amino Acid Sequence
Azoospermia / genetics
Base Sequence
Child, Preschool
Codon, Nonsense
DNA / genetics
Hearing Loss, Sensorineural / genetics
Insulin Resistance / genetics
Middle Aged
Models, Molecular
Molecular Sequence Data
Muscular Dystrophies / genetics
Mutation, Missense
Photosensitivity Disorders / genetics
RNA-Binding Proteins / chemistry,  genetics*,  metabolism
Reactive Oxygen Species / metabolism
Selenocysteine / metabolism
Selenoproteins / deficiency*,  metabolism
Sequence Homology, Amino Acid
Spermatogenesis / genetics
T-Lymphocytes / immunology
Grant Support
G0502130//Medical Research Council; G0601943//Medical Research Council; MC_U106179471//Medical Research Council
Reg. No./Substance:
0/Codon, Nonsense; 0/RNA-Binding Proteins; 0/Reactive Oxygen Species; 0/SECISBP2 protein, human; 0/Selenoproteins; 0CH9049VIS/Selenocysteine; 9007-49-2/DNA

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