Selenoprotein N-related myopathy (SEPN1-RM) is an early-onset muscle disorder that can manifest clinically as congenital muscular dystrophy with spinal rigidity and can result in specific pathological entities such as multiminicore disease, desmin-related myopathy with Mallory body-like inclusions, and congenital fiber-type disproportion. Here we describe the clinical, histopathological, muscle magnetic resonance imaging (MRI) and genetic findings of three Italian SEPN1-RM families. Proband 1 is a 31-year-old female who was floppy at birth and developed axial and mild lower limb-girdle weakness. The second proband is a 13-year-old boy with RSMD1. Probands 3 and 4 were brothers showing clinical phenotype of congenital myopathy. Muscle MRI demonstrated selective involvement of sartorius, gluteal muscles and distal gastrocnemius and sparing of rectus femoris and gracilis. Muscle histopathology showed in proband 1 myopathic changes with mild connective tissue increase and some fibres lacking the Z-line, while probands 2 and 3 had multiminicores. SEPN1 gene analysis revealed five mutations, three of which are novel. Proband 1 was a compound heterozygote for a 92-bp (exon 1) and a 1-bp deletion (exon 9); proband 2 had a 99-bp deletion and a 10-bp duplication in exon 1, and proband 3 presented a novel homozygous mutation in intron 10 acceptor splice site.
[Show abstract][Hide abstract] ABSTRACT: Selenium is an essential trace element and selenoprotein N (SelN) was the first selenium-containing protein shown to be directly involved in human inherited diseases. Mutations in the SEPN1 gene, encoding SelN, cause a group of muscular disorders characterized by predominant affection of axial muscles. SelN has been shown to participate in calcium and redox homeostasis, but its pathophysiological role in skeletal muscle remains largely unknown. To address SelN function in vivo, we generated a Sepn1-null mouse model by gene targeting. The Sepn1(-/-) mice had normal growth and lifespan, and were macroscopically indistinguishable from wild-type littermates. Only minor defects were observed in muscle morphology and contractile properties in SelN-deficient mice in basal conditions. However, when subjected to challenging physical exercise and stress conditions (forced swimming test), Sepn1(-/-) mice developed an obvious phenotype, characterized by limited motility and body rigidity during the swimming session, as well as a progressive curvature of the spine and predominant alteration of paravertebral muscles. This induced phenotype recapitulates the distribution of muscle involvement in patients with SEPN1-Related Myopathy, hence positioning this new animal model as a valuable tool to dissect the role of SelN in muscle function and to characterize the pathophysiological process.
PLoS ONE 08/2011; 6(8):e23094. DOI:10.1371/journal.pone.0023094 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1-related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the Sepn1 knock-out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1-related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1-related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options.
Journal of Molecular Medicine 04/2012; 90(10):1095-107. DOI:10.1007/s00109-012-0896-x · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The small, obscure group of selenoprotein oxidoreductases and the huge clan of kinases, the workhorses of cellular signalling, are rarely discussed together. Focusing on selenoproteins of unknown structures, we predict a thioredoxin-like fold for the Selenoprotein N (SelN) family and use the structure to rationalise effects of the muscular myopathy-linked mutations in the gene coding SelN. Discussing the recent prediction of a protein kinase-like domain in the Selenoprotein O (SelO), we reiterate evidence for a oxidoreductase function alongside the predicted kinase domain. Thus, we propose that SelO, the strongly conserved kinase-cum-tentative-oxidoreductase may reflect oxidoreductase regulation of kinase networks. Also, we use bibliometric and systems biology approach to explore the kinase-selenoprotein relationships that begin to emerge from the literatura. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
Roula Ghaoui, Sandra T Cooper, Monkol Lek, Kristi Jones, Alastair Corbett, Stephen W Reddel, Merrilee Needham, Christina Liang, Leigh B Waddell, Garth Nicholson, Gina O'Grady, Simranpreet Kaur, Royston Ong, Mark Davis, Carolyn M Sue, Nigel G Laing, Kathryn N North, Daniel G MacArthur, Nigel F Clarke
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