A single homozygous point mutation in a 3′untranslated region motif of selenoprotein N mRNA causes SEPN1‐related myopathy

Allamand, Valérie; Richard, Pascale; Lescure, Alain; Ledeuil, C.; Desjardin, Delphine; Petit, Nathalie; Gartioux, C.; Ferreiro, Ana; Krol, Alain; Pellegrini, N.; Urtizberea, Jon Andoni; Guicheney, Pascale

doi:10.1038/sj.embor.7400648

Cited by 89 publications

(55 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Among these are a nonsense mutation (1370C-4T), a homozygous 20 bp duplication in exon 1 and a 1 nucleotide insertion at position 1, that are all predicted to result in a truncated protein which should be degraded via the nonsense-mediated decay pathway. More recently, a point mutation within the SECIS domain of the hairpin-containing 3 0 -untranslated region of SEPN1 mRNA was found (20). The latter mutation, together with mutations affecting the initiation codon or insertions within exon 1, were shown to significantly diminish the level of SEPN1 expressed in cultured fibroblasts (20), confirming that mRNA degradation occurs when the transcript is terminated prematurely or when the SECIS complex can not properly assemble and direct read-through the internal UGA selenocysteine-encoding, termination codon.…”

Section: Mutations In the Selenoprotein N (Sepn1) Genementioning

confidence: 99%

Functional effects of mutations identified in patients with Multiminicore disease

Zorzato¹,

Jungbluth²,

Zhou³

et al. 2007

IUBMB Life

View full text Add to dashboard Cite

SummaryMultiminicore disease is a recessive congenital myopathy characterized by the presence of small cores or areas lacking oxidative enzymes, in skeletal muscle fibres. From a clinical point of view, the condition is widely heterogeneous and at least four phenotypes have been identified; genetic analysis has revealed that most patients with the classical form of multiminicore characterized by rigidity of the spine, early onset and respiratory impairment harbour recessive mutations in the SEPN1 gene, whereas the majority of patients belonging to the other categories, including patients with ophthalmoplegia or patients with a phenotype similar to central core disease, carry recessive mutations in the RYR1. In the present review we discuss the most recent findings on the functional effect of mutations in SEPN1 and RYR1 and discuss how they may adversely affect muscle function and lead to the clinical phenotype.

show abstract

Section: Mutations In the Selenoprotein N (Sepn1) Genementioning

confidence: 99%

Functional effects of mutations identified in patients with Multiminicore disease

Zorzato¹,

Jungbluth²,

Zhou³

et al. 2007

IUBMB Life

View full text Add to dashboard Cite

show abstract

“…The SePN-1 related myopathies are a group of early onset congenital muscular dystrophies in humans that result from different mutations in the selenoprotein N (SelN) gene (19 -23). Rigid spine muscular dystrophy, one member of this group, can be caused by a point mutation in the SECIS of SelN mRNA that abolishes SBP2 binding, resulting in the loss of SelN expression (24). The deiodinases are required for human thyroid hormone homeostasis, and mutations in SBP2 that are linked to thyroid dysfunction in humans were recently reported in two different families (25).…”

mentioning

confidence: 99%

Altered RNA Binding Activity Underlies Abnormal Thyroid Hormone Metabolism Linked to a Mutation in Selenocysteine Insertion Sequence-binding Protein 2

Bubenik

Driscoll

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The expression of selenoproteins requires the translational recoding of the UGA stop codon to selenocysteine. In eukaryotes, this requires an RNA stem loop structure in the 3-untranslated region, termed a selenocysteine insertion sequence (SECIS), and SECIS-binding protein 2 (SBP2). This study implicates SBP2 in dictating the hierarchy of selenoprotein expression, because it is the first to show that SBP2 distinguishes between SECIS elements in vitro. Using RNA electrophoretic mobility shift assays, we demonstrate that a naturally occurring mutation in SBP2, which correlates with abnormal thyroid hormone function in humans, lies within a novel, bipartite RNA-binding domain. This mutation alters the RNA binding affinity of SBP2 such that it no longer stably interacts with a subset of SECIS elements. Assays performed under competitive conditions to mimic intracellular conditions suggest that the differential affinity of SBP2 for various SECIS elements will determine the expression pattern of the selenoproteome. We hypothesize that the selective loss of a subset of selenoproteins, including some involved in thyroid hormone homeostasis, is responsible for the abnormal thyroid hormone metabolism previously observed in the affected individuals.Selenium is an essential micronutrient for human health. Most of the selenium in the body is found as selenocysteine, which is incorporated into proteins termed selenoproteins. Selenoproteins are believed to be involved in such diverse aspects of human health as immunity, fertility, cancer prevention, and atherosclerosis (1). The human selenoproteome is composed of ϳ25 members (2). Those of known function include the glutathione peroxidases, the thioredoxin reductases, and the deiodinases, all of which are involved in oxidation-reduction reactions within cells (3, 4).Selenoprotein synthesis is unusual, because it relies on the translational recoding of a UGA stop codon to selenocysteine within the coding region of selenoprotein mRNAs. The dual nature of this codon implies that chain termination and selenocysteine insertion are competing processes; however, this area remains poorly understood at this time. In recent years, much progress has been made in delineating the necessary components for selenocysteine incorporation. This process requires an RNA stem-loop structure termed the selenocysteine insertion sequence (SECIS), 2 which is located in the 3Ј-untranslated region of eukaryotic selenoprotein mRNAs (5). In addition, a selenocysteine-charged tRNA (Sec-tRNA Sec ) (6) and an elongation factor dedicated to selenocysteine insertion (EFSec) (7,8) are necessary. Several other protein factors have roles in SectRNA Sec synthesis and delivery, and interactions between the selenoprotein mRNA, Sec-tRNA Sec , and the ribosome have also been identified. Currently, the exact order of events and series of interactions remains unclear. For a comprehensive review of selenocysteine insertion see reviews by Hatfield and Gladyshev (9) and Hoffman and Berry (10).Our lab has a long standing inte...

show abstract

“…Another example of SECIS mutations was recently reported in the SelN gene (SEPN1), and in this case, the phenotype was far more dramatic (4). It has been well documented that mutations within the SelN gene (SEPN1) cause earlyonset muscular disorders, in some cases leading to fatal respiratory failure (discussed in detail in the selenoprotein N section).…”

Section: From Selenium To Selenoproteins 779mentioning

confidence: 98%

Untitled

2007

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

A single homozygous point mutation in a 3′untranslated region motif of selenoprotein N mRNA causes SEPN1‐related myopathy

Cited by 89 publications

References 28 publications

Functional effects of mutations identified in patients with Multiminicore disease

Functional effects of mutations identified in patients with Multiminicore disease

Altered RNA Binding Activity Underlies Abnormal Thyroid Hormone Metabolism Linked to a Mutation in Selenocysteine Insertion Sequence-binding Protein 2

Untitled

Contact Info

Product

Resources

About