Article

New molecular findings in congenital myopathies due to selenoprotein N gene mutations

Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy.
Journal of the neurological sciences (Impact Factor: 2.47). 10/2010; 300(1-2):107-13. DOI: 10.1016/j.jns.2010.09.011
Source: PubMed

ABSTRACT

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.

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    ABSTRACT: Selenoprotein N is among the newly identified selenoproteins, initially discovered in silico with no known molecular function. It has become the focus of attention because mutations in the selenoprotein N gene are linked to a group of muscle disorders, now referred as SEPN1-related myopathies. An emerging view arising from recent findings is that the loss of selenoprotein N leads to cellular sensitivity to oxidative stress and loss of calcium homeostasis. Studies of animal models for SEPN1-Related Myopathies revealed the fate of sensitized muscle may depend on stresses to which it is subjected, and defects in the function of selenoprotein N-deficient muscle progenitor cells during development in zebrafish embryos or during muscle regeneration in fully developed mouse muscle. Dysfunction of these different processes raises significant questions regarding which of the phenotypic manifestations of SEPN1-Related Myopathies are initiated by events during development and which are progressive in nature arising from dysfunction of mature muscle.
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    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.
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