A single homozygous point mutation in a 3'untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy.
Mutations in the SEPN1 gene encoding the selenoprotein N (SelN) have been described in different congenital myopathies. Here, we report the first mutation in the selenocysteine insertion sequence (SECIS) of SelN messenger RNA, a hairpin structure located in the 3' untranslated region, in a patient presenting a classical although mild form of rigid spine muscular dystrophy. We detected a significant reduction in both mRNA and protein levels in the patient's skin fibroblasts. The SECIS element is crucial for the insertion of selenocysteine at the reprogrammed UGA codon by recruiting the SECIS-binding protein 2 (SBP2), and we demonstrated that this mutation abolishes SBP2 binding to SECIS in vitro, thereby preventing co-translational incorporation of selenocysteine and SelN synthesis. The identification of this mutation affecting a conserved base in the SECIS functional motif thereby reveals the structural basis for a novel pathological mechanism leading to SEPN1-related myopathy.
Allamand
Valérie
V
Institut National de la Santé et de la Recherche Médicale, U582, Institut de Myologie, IFR 14, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. v.allamand@myologie.chups.jussieu.fr
Richard
Pascale
P
Lescure
Alain
A
Ledeuil
Céline
C
Desjardin
Delphine
D
Petit
Nathalie
N
Gartioux
Corine
C
Ferreiro
Ana
A
Krol
Alain
A
Pellegrini
Nadine
N
Urtizberea
J Andoni
JA
Guicheney
Pascale
P
D020413:3' Untranslated Regions / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism; D051140:Selenoproteins / Q000235:genetics* / Q000378:metabolism*
D020413:3' Untranslated Regions; D016601:RNA-Binding Proteins; C121530:SECISBP2 protein, human; D051140:Selenoproteins