title: 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.
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.forename: Catherine
authors.initials: C
authors.lastname: Mitchell
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: Laura
authors.initials: L
authors.lastname: Papp
authors.forename: Odelia
authors.initials: O
authors.lastname: Rajanayagam
authors.forename: Raja
authors.initials: R
authors.lastname: Padidela
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ceron-Gutierrez
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Claudia
authors.initials: C
authors.lastname: Prevosto
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Sergio
authors.initials: S
authors.lastname: Montano
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Mireille
authors.initials: M
authors.lastname: Castanet
authors.forename: Nick
authors.initials: N
authors.lastname: Clemons
authors.forename: Matthijs
authors.initials: M
authors.lastname: Groeneveld
authors.forename: Perrine
authors.initials: P
authors.lastname: Castets
authors.forename: Mahsa
authors.initials: M
authors.lastname: Karbaschi
authors.forename: Sri
authors.initials: S
authors.lastname: Aitken
authors.forename: Adrian
authors.initials: A
authors.lastname: Dixon
authors.forename: Jane
authors.initials: J
authors.lastname: Williams
authors.forename: Irene
authors.initials: I
authors.lastname: Campi
authors.forename: Margaret
authors.initials: M
authors.lastname: Blount
authors.forename: Hannah
authors.initials: H
authors.lastname: Burton
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Dominic
authors.initials: D
authors.lastname: O'Donovan
authors.forename: Andrew
authors.initials: A
authors.lastname: Dean
authors.forename: Anne
authors.initials: A
authors.lastname: Warren
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brierley
authors.forename: David
authors.initials: D
authors.lastname: Baguley
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fitzgerald
authors.forename: Alasdair
authors.initials: A
authors.lastname: Coles
authors.forename: Hill
authors.initials: H
authors.lastname: Gaston
authors.forename: Pamela
authors.initials: P
authors.lastname: Todd
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Marcus
authors.initials: M
authors.lastname: Cooke
authors.forename: Robert
authors.initials: R
authors.lastname: Semple
authors.forename: David
authors.initials: D
authors.lastname: Halsall
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.forename: John
authors.initials: J
authors.lastname: Schwabe
authors.forename: Lucia
authors.initials: L
authors.lastname: Grasso
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Arthur
authors.initials: A
authors.lastname: Ogunko
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D053713:Azoospermia / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010787:Photosensitivity Disorders / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017279:Selenocysteine / Q000378:metabolism; D051140:Selenoproteins / Q000172:deficiency* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013091:Spermatogenesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018389:Codon, Nonsense; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C121530:SECISBP2 protein, human; D051140:Selenoproteins; D017279:Selenocysteine; D004247:DNA