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

Cagliani, Rachele; Fruguglietti, M.E.; Berardinelli, Angela; Prelle, A.; Riva, Stefania; Napoli, Laura; Gorni, Ksenija; Orcesi, Simona; Lamperti, Costanza; Pichiecchio, Anna; Signaroldi, E.; Tupler, Rossella; Magri, Francesca; Govoni, Alessandra; Corti, Stefania; Bresolin, Nereo; Moggio, Maurizio; Comi, Giacomo P.

doi:10.1016/j.jns.2010.09.011

Cited by 24 publications

(12 citation statements)

References 32 publications

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“…Accordingly, the EM examination showed a few fields, mainly located at the center of the fibers, devoid of mitochondria. In these areas, the sarcomeric organization was quite normal, though the Z lines were often absent (Figure S3) as reported in selenoprotein‐related diseases (Cagliani et al, ), or somewhat irregular (Figures S5 and S6). Interestingly, at EM the areas devoid of mitochondria did not show any major misalignment such as streaming of the Z bands, that is well known to occur in the cores which are typically devoid of oxidative stains in RYR1 related myopathies (Monnier et al, ).…”

Section: Discussionsupporting

confidence: 60%

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

et al. 2019

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Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting Human Mutation. 2019;40:601-618.wileyonlinelibrary.com/journal/humu

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Section: Discussionsupporting

confidence: 60%

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

et al. 2019

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“…SEPN1-related myopathy is a congenital muscular disorder arising from loss-of-function mutations in the SELENON gene [32,33]. Here, we show abnormalities in the glucose metabolism of patients with SEPN1-related myopathy that suggest insulin resistance.…”

Section: Discussionmentioning

confidence: 70%

SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance

et al. 2019

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Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a congenital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON - devoid cells, and blunt the insulin-mediated glucose uptake of SELENON - devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations.

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“…SELENON-related myopathies are a group of congenital disorders arising from loss-of-function mutations in the SELENON gene that affect the muscle system, and lead to life-threatening respiratory malfunction, requiring assisted ventilation, with relative preservation of limb muscles and ambulation [23] , [7] . No FDA-approved drugs are currently available for SELENON-RMs, so clarifying their pathogenic mechanisms is an important step towards developing a pharmacological treatment.…”

Section: Discussionmentioning

confidence: 99%

A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss

et al. 2019

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Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to human SELENON-related myopathies. SelenoN knockout (KO) mouse limb muscles, however, are protected from the disease, and display no major alterations in muscle histology or contractile properties. Interestingly, we find that the highly active diaphragm muscle shows impaired force production, in line with the human phenotype. In addition, after repeated stimulation with a protocol which induces muscle fatigue, also hind limb muscles show altered relaxation times. Mechanistically, muscle SELENON loss alters activity-dependent calcium handling selectively impinging on the Ca2+ uptake of the sarcoplasmic reticulum and elicits an ER stress response, including the expression of the maladaptive CHOP-induced ERO1. In SELENON-devoid models, ERO1 shifts ER redox to a more oxidised poise, and further affects Ca2+ uptake. Importantly, CHOP ablation in SelenoN KO mice completely prevents diaphragm dysfunction, the prolonged limb muscle relaxation after fatigue, and restores Ca2+ uptake by attenuating the induction of ERO1. These findings suggest that SELENON is part of an ER stress-dependent antioxidant response and that the CHOP/ERO1 branch of the ER stress response is a novel pathogenic mechanism underlying SELENON-related myopathies.

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

Cited by 24 publications

References 32 publications

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance

A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss

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