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EMBO reports 7, 4, 450–454 (2006)
doi:10.1038/sj.embor.7400648
AOP Published online: 24 February 2006
A single homozygous point mutation in a 3'untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy
Valérie Allamand1, 2, 6, Pascale Richard1, 2, 3, 6, Alain Lescure4, Céline Ledeuil3, Delphine Desjardin3, Nathalie Petit1, 2, Corine Gartioux1, 2, Ana Ferreiro1, 2, Alain Krol4, Nadine Pellegrini5, J Andoni Urtizberea5 & Pascale Guicheney1, 2
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1 Institut National de la Santé et de la Recherche Médicale, U582, Institut de Myologie, IFR 14, Groupe Hospitalier Pitié-Salpêtrière, Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
2 Université Pierre et Marie Curie, 4 Place Jussieu, 75250 Paris Cedex 05, France
3 Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, UF Cardiogénétique et Myogénétique, Service de Biochimie B, 47 Boulevard de l'Hôpital, 756511 Paris Cedex 13, France
4 CNRS-Université Louis Pasteur, UPR 9002, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg, France
5 Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France
6 These authors contributed equally to this work
To whom correspondence should be addressed
Valérie Allamand Tel: +33 1 42165743; Fax: +33 1 42165700; E-mail: v.allamand@myologie.chups.jussieu.fr
Received 2 September 2005; Accepted 23 January 2006; Published online 24 February 2006.
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Abstract
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.
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