The Beggs Laboratory|SELENON Related Myopathies

The SELENON (formally SEPN1) Related Myopathies (SELENON-RM)  are a group of rare congenital myopathies which alter an individual’s ability to synthesize Selenoprotein N (Moghadaszadeh et al. 2001Ferreiro et al. 2002; Castets et al. 2009; Lescure et al. 2009; Marino et al. 2015; Moghadaszadeh et al. 2013). Selenoprotein N belongs to the group of selenoproteins, which thanks to several cis and trans elements, all have the ability to incorporate the amino acid selenocysteine (Sec) at a UGA codon (Seeher, Mahdi, and Schweizer 2012). Anomalies at any of the cis and/or trans elements would result in a stop codon and premature termination of protein synthesis  (Castets et al. 2009Gladyshev et al. 2016Seeher, Mahdi, and Schweizer 2012). Selenoprotein N is more prominent in fetal as compared to adult tissues, and can be found throughout the body (Castets et al. 2009; Gladyshev et al. 2016; Lescure et al. 2009). Though not all biological roles of SELENON are understood, researchers have found it to significantly impact the calcium flux in the cells through redox regulation of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA), which in turn seems to considerably affect skeletal muscles (Appenzeller-Herzog and Simmen 2016Castets et al. 2009Deniziak et al. 2007 Marino et al. 2015; Moghadaszadeh et al. 2013).

 

A diagram illustrating how SELENON is thought to interact with SERCA to facilitate calcium ions re-uptake by the sarcoplasmic reticulum after a muscle cell contraction.

 

Genetics & Pathology 

Pathologically speaking, SELENON-RM may present as a few different conditions observed in muscle biopsies from affected individuals including multiminicores, fiber type disproportion, and Mallory-bodies (Clarke et al. 2006DeChene, Kang, and Beggs 1993Ferreiro et al. 2002Ferreiro et al. 2004). The SELENON gene, found in 2001, is located chromosome 1 at position p36.1 (Moghadaszadeh et al. 2001). Mutations in the SELENON gene, which are inherited in an autosomal recessive pattern, can result in the presentation of a wide range of symptoms, severities, and time of onset (Ferreiro et al. 2002Scoto et al. 2011Pozzer et al. 2017). By far, the most common symptoms of SELENON-RM affected individuals include respiratory insufficiency (primarily during sleep), spinal (and neck) rigidity, and axial muscle weakness (Ferreiro et al. 2002Scoto et al. 2011Nadaj-Pakleza et al. 2007; Moghadaszadehet al. 2013Rederstorff et al. 2011).

 


Various muscle cells exhibiting different pathological findings that all fall under the umbrella term of SELENON Related Myopathies; top left: CFTD; top right: Multiminicore myopathy; bottom left: areas lacking mitochondria (light spots in the dark purple cells);  bottom right: CFTD.

 

Research

Researchers have produced several zebrafish and mouse models lacking SELENON (either permanently or transiently). Unfortunately, these models do not seem to replicate symptoms observed in human patients. While some research in zebrafish with reduced  levels of SELENON found muscle fiber disorganization, other research in zebrafish with complete deficiency of SELENON failed to observe any symptoms or changes compared to normal zebrafish (Deniziak et al. 2007). Mice lacking the ability to make SELENON, showed very mild muscle phenotypes only when subjected to very strenuous exercises (Behzad Moghadaszadeh et al. 2013, Rederstorff et al. 2011). However, these mice manifested an alveolar enlargement in their lungs raising the question whether a similar phenotype may be present in human patients (Behzad Moghadaszadeh et al. 2013). Further research is needed to develop robust cellular and animal models that will be used in the short term to better understand the function of SELENON and develop efficient therapies in the long term.

 

Two mouse lung tissue sections showing enlarged alveoli in the SELENON knockout mice (seen on the right) compared to the wild type mouse (on the left).

 

References

Appenzeller-Herzog, C. and T. Simmen. "Er-Luminal Thiol/Selenol-Mediated Regulation of Ca2+ Signalling." Biochem Soc Trans 44, no. 2 (2016): 452-9.

Castets, P., S. Maugenre, C. Gartioux, M. Rederstorff, A. Krol, A. Lescure, S. Tajbakhsh, V. Allamand, and P. Guicheney. "Selenoprotein N Is Dynamically Expressed During Mouse Development and Detected Early in Muscle Precursors." BMC Dev Biol 9 (2009): 46.

Clarke, N. F., W. Kidson, S. Quijano-Roy, B. Estournet, A. Ferreiro, P. Guicheney, J. I. Manson, A. J. Kornberg, L. K. Shield, and K. N. North. "Sepn1: Associated with Congenital Fiber-Type Disproportion and Insulin Resistance." Ann Neurol 59, no. 3 (2006): 546-52.

DeChene, E. T., P. B. Kang, and A. H. Beggs. "Congenital Fiber-Type Disproportion." In Genereviews((R)), edited by M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, and A. Amemiya. Seattle (WA): University of Washington, Seattle. University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved., 1993.

Deniziak, M., C. Thisse, M. Rederstorff, C. Hindelang, B. Thisse, and A. Lescure. "Loss of Selenoprotein N Function Causes Disruption of Muscle Architecture in the Zebrafish Embryo." Exp Cell Res 313, no. 1 (2007): 156-67.

Ferreiro, A., C. Ceuterick-de Groote, J. J. Marks, N. Goemans, G. Schreiber, F. Hanefeld, M. Fardeau, J. J. Martin, H. H. Goebel, P. Richard, P. Guicheney, and C. G. Bonnemann. "Desmin-Related Myopathy with Mallory Body-Like Inclusions Is Caused by Mutations of the Selenoprotein N Gene." Ann Neurol 55, no. 5 (2004): 676-86.

Ferreiro, A., S. Quijano-Roy, C. Pichereau, B. Moghadaszadeh, N. Goemans, C. Bonnemann, H. Jungbluth, V. Straub, M. Villanova, J. P. Leroy, N. B. Romero, J. J. Martin, F. Muntoni, T. Voit, B. Estournet, P. Richard, M. Fardeau, and P. Guicheney. "Mutations of the Selenoprotein N Gene, Which Is Implicated in Rigid Spine Muscular Dystrophy, Cause the Classical Phenotype of Multiminicore Disease: Reassessing the Nosology of Early-Onset Myopathies." Am J Hum Genet 71, no. 4 (2002): 739-49.

Gladyshev, V. N., E. S. Arner, M. J. Berry, R. Brigelius-Flohe, E. A. Bruford, R. F. Burk, B. A. Carlson, S. Castellano, L. Chavatte, M. Conrad, P. R. Copeland, A. M. Diamond, D. M. Driscoll, A. Ferreiro, L. Flohe, F. R. Green, R. Guigo, D. E. Handy, D. L. Hatfield, J. Hesketh, P. R. Hoffmann, A. Holmgren, R. J. Hondal, M. T. Howard, K. Huang, H. Y. Kim, I. Y. Kim, J. Kohrle, A. Krol, G. V. Kryukov, B. J. Lee, B. C. Lee, X. G. Lei, Q. Liu, A. Lescure, A. V. Lobanov, J. Loscalzo, M. Maiorino, M. Mariotti, K. Sandeep Prabhu, M. P. Rayman, S. Rozovsky, G. Salinas, E. E. Schmidt, L. Schomburg, U. Schweizer, M. Simonovic, R. A. Sunde, P. A. Tsuji, S. Tweedie, F. Ursini, P. D. Whanger, and Y. Zhang. "Selenoprotein Gene Nomenclature." J Biol Chem 291, no. 46 (2016): 24036-40.

Lescure, A., M. Rederstorff, A. Krol, P. Guicheney, and V. Allamand. "Selenoprotein Function and Muscle Disease." Biochim Biophys Acta 1790, no. 11 (Nov 2009): 1569-74.

Marino, M., T. Stoilova, C. Giorgi, A. Bachi, A. Cattaneo, A. Auricchio, P. Pinton, and E. Zito. "Sepn1, an Endoplasmic Reticulum-Localized Selenoprotein Linked to Skeletal Muscle Pathology, Counteracts Hyperoxidation by Means of Redox-Regulating Serca2 Pump Activity." Human Molecular Genetics 24, no. 7 (2015): 1843-55.

Moghadaszadeh, B., N. Petit, C. Jaillard, M. Brockington, S. Quijano Roy, L. Merlini, N. Romero, B. Estournet, I. Desguerre, D. Chaigne, F. Muntoni, H. Topaloglu, and P. Guicheney. "Mutations in Sepn1 Cause Congenital Muscular Dystrophy with Spinal Rigidity and Restrictive Respiratory Syndrome." Nat Genet 29, no. 1 (2001): 17-8.

Moghadaszadeh, B., B. E. Rider, M. W. Lawlor, M. K. Childers, R. W. Grange, K. Gupta, S. S. Boukedes, C. A. Owen, and A. H. Beggs. "Selenoprotein N Deficiency in Mice Is Associated with Abnormal Lung Development." Faseb j 27, no. 4 (2013): 1585-99.

Nadaj-Pakleza, A., A. Fidzianska, B. Ryniewicz, A. Kostera-Pruszczyk, A. Ferreiro, H. Kwiecinski, and A. Kaminska. "Multi-Minicore Myopathy: A Clinical and Histopathological Study of 17 Cases." Folia Neuropathol 45, no. 2 (2007): 56-65.

Pozzer, D., M. Favellato, M. Bolis, R. W. Invernizzi, F. Solagna, B. Blaauw, and E. Zito. "Endoplasmic Reticulum Oxidative Stress Triggers Tgf-Beta-Dependent Muscle Dysfunction by Accelerating Ascorbic Acid Turnover." Scientific Reports 7 (01/20/online 2017): 40993.

Rederstorff, M., P. Castets, S. Arbogast, J. Lainé, S. Vassilopoulos, M. Beuvin, O. Dubourg, A. Vignaud, A. Ferry, A. Krol, V. Allamand, P. Guicheney, A. Ferreiro, and A. Lescure. "Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian Model for Sepn1-Related Myopathy." PLOS ONE 6, no. 8 (2011): e23094.

Scoto, M., S. Cirak, R. Mein, L. Feng, A. Y. Manzur, S. Robb, A. M. Childs, R. M. Quinlivan, H. Roper, D. H. Jones, C. Longman, G. Chow, M. Pane, M. Main, M. G. Hanna, K. Bushby, C. Sewry, S. Abbs, E. Mercuri, and F. Muntoni. "Sepn1-Related Myopathies: Clinical Course in a Large Cohort of Patients." Neurology 76, no. 24 (2011): 2073-8.

Seeher, S., Y. Mahdi, and U. Schweizer. "Post-Transcriptional Control of Selenoprotein Biosynthesis." Curr Protein Pept Sci 13, no. 4 (2012): 337-46.

 

This page was last updated May 28, 2020.