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1,078 results on '"Wallgren‐Pettersson, Carina"'

2. A cross-sectional study in 18 patients with typical and mild forms of nemaline myopathy in the Netherlands

Author

van Kleef, Esmee S.B., van de Camp, Sanne A.J.H., Groothuis, Jan T., Erasmus, Corrie E., Gaytant, Michael A., Vosse, Bettine A.H., de Weerd, Willemien, Verschuuren-Bemelmans, Corien C., Medici-Van den Herik, Evita G., Wallgren-Pettersson, Carina, Küsters, Benno, Schouten, Meyke, van Engelen, Baziel G.M., Ottenheijm, Coen A.C., Doorduin, Jonne, and Voermans, Nicol C.

Published
2024
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6. NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

Author

Ranu, Natasha, Laitila, Jenni, Dugdale, Hannah F., Mariano, Jennifer, Kolb, Justin S., Wallgren-Pettersson, Carina, Witting, Nanna, Vissing, John, Vilchez, Juan Jesus, Fiorillo, Chiara, Zanoteli, Edmar, Auranen, Mari, Jokela, Manu, Tasca, Giorgio, Claeys, Kristl G., Voermans, Nicol C., Palmio, Johanna, Huovinen, Sanna, Moggio, Maurizio, Beck, Thomas Nyegaard, Kontrogianni-Konstantopoulos, Aikaterini, Granzier, Henk, and Ochala, Julien

Published
2022
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7. Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin‐deficient muscle.

Author

Laitila, Jenni, Seaborne, Robert A. E., Ranu, Natasha, Kolb, Justin S., Wallgren‐Pettersson, Carina, Witting, Nanna, Vissing, John, Vilchez, Juan Jesus, Zanoteli, Edmar, Palmio, Johanna, Huovinen, Sanna, Granzier, Henk, and Ochala, Julien

Subjects
MYOSIN, METABOLISM, PROTEOMICS, NEBULIN, CYTOPLASMIC filaments
Abstract

Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB‐NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super‐relaxed state was significantly impaired in NEB‐NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small‐molecule Mavacamten is known to promote the myosin super‐relaxed state and reduce the ATP demand, we tested its potency in the context of NEB‐NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short‐term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild‐type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short‐term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short‐term efficacy in vivo. Key points: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins.Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane‐permeabilized muscle fibres from human patients restored myosin energetic disturbances.Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins.Short‐term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle

Author

Laitila, Jenni, primary, Seaborne, Robert, additional, Ranu, Natasha, additional, Kolb, Justin, additional, Wallgren-Pettersson, Carina, additional, Witting, Nanna, additional, Vissing, John, additional, Vilchez, Juan Jesus, additional, Zanoteli, Edmar, additional, Palmio, Johanna, additional, Huovinen, Sanna, additional, Granzier, Henk, additional, and Ochala, Julien, additional

Published
2024
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10. A clinical scoring system for congenital contractural arachnodactyly

Author

Meerschaut, Ilse, De Coninck, Shana, Steyaert, Wouter, Barnicoat, Angela, Bayat, Allan, Benedicenti, Francesco, Berland, Siren, Blair, Edward M., Breckpot, Jeroen, de Burca, Anna, Destrée, Anne, García-Miñaúr, Sixto, Green, Andrew J., Hanna, Bernadette C., Keymolen, Kathelijn, Koopmans, Marije, Lederer, Damien, Lees, Melissa, Longman, Cheryl, Lynch, Sally Ann, Male, Alison M., McKenzie, Fiona, Migeotte, Isabelle, Mihci, Ercan, Nur, Banu, Petit, Florence, Piard, Juliette, Plasschaert, Frank S., Rauch, Anita, Ribaï, Pascale, Pacheco, Iratxe Salcedo, Stanzial, Franco, Stolte-Dijkstra, Irene, Valenzuela, Irene, Varghese, Vinod, Vasudevan, Pradeep C., Wakeling, Emma, Wallgren-Pettersson, Carina, Coucke, Paul, De Paepe, Anne, De Wolf, Daniël, Symoens, Sofie, and Callewaert, Bert

Published
2020
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13. Novel Compound Heterozygous Splice-Site Variants in TPM3 Revealed by RNA Sequencing in a Patient with an Unusual Form of Nemaline Myopathy: A Case Report

Author

Pelin, Katarina, primary, Sagath, Lydia, additional, Lehtonen, Johanna, additional, Kiiski, Kirsi, additional, Tynninen, Olli, additional, Paetau, Anders, additional, Johari, Mridul, additional, Savarese, Marco, additional, Wallgren-Pettersson, Carina, additional, and Lehtokari, Vilma-Lotta, additional

Published
2023
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16. Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy

Author

Ross, Jacob A., Levy, Yotam, Ripolone, Michela, Kolb, Justin S., Turmaine, Mark, Holt, Mark, Lindqvist, Johan, Claeys, Kristl G., Weis, Joachim, Monforte, Mauro, Tasca, Giorgio, Moggio, Maurizio, Figeac, Nicolas, Zammit, Peter S., Jungbluth, Heinz, Fiorillo, Chiara, Vissing, John, Witting, Nanna, Granzier, Henk, Zanoteli, Edmar, Hardeman, Edna C., Wallgren-Pettersson, Carina, and Ochala, Julien

Published
2019
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19. Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Author

Laitila, Jenni M., McNamara, Elyshia L., Wingate, Catherine D., Goullee, Hayley, Ross, Jacob A., Taylor, Rhonda L., van der Pijl, Robbert, Griffiths, Lisa M., Harries, Rachel, Ravenscroft, Gianina, Clayton, Joshua S., Sewry, Caroline, Lawlor, Michael W., Ottenheijm, Coen A. C., Bakker, Anthony J., Ochala, Julien, Laing, Nigel G., Wallgren-Pettersson, Carina, Pelin, Katarina, and Nowak, Kristen J.

Published
2020
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20. Variants in tropomyosins TPM2 and TPM3 causing muscle hypertonia.

Author

Wallgren-Pettersson, Carina, Jokela, Manu, Lehtokari, Vilma-Lotta, Tyynismaa, Henna, Sainio, Markus T, Ylikallio, Emil, Tynninen, Olli, Pelin, Katarina, and Auranen, Mari

Subjects
*NEMALINE myopathy, *TROPOMYOSINS, *MUSCLE weakness, *MUSCLE hypotonia, *MUSCLE tone, *FINGER joint, *THUMB
Abstract

• Novel clinical finding of muscle hypertonia in tropomyosin-caused congenital myopathy. • Unusual symptom of trismus. • Unspecific histological findings. Patients with myopathies caused by pathogenic variants in tropomyosin genes TPM2 and TPM3 usually have muscle hypotonia and weakness, their muscle biopsies often showing fibre size disproportion and nemaline bodies. Here, we describe a series of patients with hypercontractile molecular phenotypes, high muscle tone, and mostly non-specific myopathic biopsy findings without nemaline bodies. Three of the patients had trismus, whilst in one patient, the distal joints of her fingers flexed on extension of the wrists. In one biopsy from a patient with a rare TPM3 pathogenic variant, cores and minicores were observed, an unusual finding in TPM3 -caused myopathy. The variants alter conserved contact sites between tropomyosin and actin. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Mutations in the Nebulin Gene Associated with Autosomal Recessive Nemaline Myopathy

Author

Pelin, Katarina, Hilpela, Pirta, Donner, Kati, Sewry, Caroline, Akkari, Patrick A., Wilton, Stephen D., Wattanasirichaigoon, Duangrurdee, Bang, Marie-Louise, Centner, Thomas, Hanefeld, Folker, Odent, Sylvie, Fardeau, Michel, Urtizberea, J. Andoni, Muntoni, Francesco, Dubowitz, Victor, Beggs, Alan H., Laing, Nigel G., Labeit, Siegfried, de la Chapelle, Albert, and Wallgren-Pettersson, Carina

Published
1999

23. Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization

Author

Gurgel-Giannetti, Juliana, primary, Souza, Lucas Santos, additional, Yamamoto, Guilherme L., additional, Belisario, Marina, additional, Lazar, Monize, additional, Campos, Wilson, additional, Pavanello, Rita de Cassia M., additional, Zatz, Mayana, additional, Reed, Umbertina, additional, Zanoteli, Edmar, additional, Oliveira, Acary Bulle, additional, Lehtokari, Vilma-Lotta, additional, Casella, Erasmo B., additional, Machado-Costa, Marcela C., additional, Wallgren-Pettersson, Carina, additional, Laing, Nigel G., additional, Nigro, Vincenzo, additional, and Vainzof, Mariz, additional

Published
2022
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24. Nebulin—A Giant Chameleon

Author

Pelin, Katarina, Wallgren-Pettersson, Carina, Back, Nathan, editor, Cohen, Irun R., editor, Lajtha, Abel, editor, Lambris, John D., editor, Paoletti, Rodolfo, editor, and Laing, Nigel G., editor

Published
2008
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26. Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Author

Johnson, Katherine, Bertoli, Marta, Phillips, Lauren, Töpf, Ana, Van den Bergh, Peter, Vissing, John, Witting, Nanna, Nafissi, Shahriar, Jamal-Omidi, Shirin, Łusakowska, Anna, Kostera-Pruszczyk, Anna, Potulska-Chromik, Anna, Deconinck, Nicolas, Wallgren-Pettersson, Carina, Strang-Karlsson, Sonja, Colomer, Jaume, Claeys, Kristl G., De Ridder, Willem, Baets, Jonathan, von der Hagen, Maja, Fernández-Torrón, Roberto, Zulaica Ijurco, Miren, Espinal Valencia, Juan Bautista, Hahn, Andreas, Durmus, Hacer, Willis, Tracey, Xu, Liwen, Valkanas, Elise, Mullen, Thomas E., Lek, Monkol, MacArthur, Daniel G., and Straub, Volker

Published
2018
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28. Novel Compound Heterozygous Splice-Site Variants in TPM3Revealed by RNA Sequencing in a Patient with an Unusual Form of Nemaline Myopathy: A Case Report

Author

Pelin, Katarina, Sagath, Lydia, Lehtonen, Johanna, Kiiski, Kirsi, Tynninen, Olli, Paetau, Anders, Johari, Mridul, Savarese, Marco, Wallgren-Pettersson, Carina, and Lehtokari, Vilma-Lotta

Abstract

Pathogenic variants in the TPM3gene, encoding slow skeletal muscle α-tropomyosin account for less than 5% of nemaline myopathy cases. Dominantly inherited or de novomissense variants in TPM3are more common than recessive loss-of-function variants. The recessive variants reported to date seem to affect either the 5’ or the 3’ end of the skeletal muscle-specific TPM3transcript. The aim of the study was to identify the disease-causing gene and variants in a Finnish patient with an unusual form of nemaline myopathy. The genetic analyses included Sanger sequencing, whole-exome sequencing, targeted array-CGH, and linked-read whole genome sequencing. RNA sequencing was done on total RNA extracted from cultured myoblasts and myotubes of the patient and controls. TPM3 protein expression was assessed by Western blot analysis. The diagnostic muscle biopsy was analyzed by routine histopathological methods. The patient had poor head control and failure to thrive, but no hypomimia, and his upper limbs were clearly weaker than his lower limbs, features which in combination with the histopathology suggested TPM3-caused nemaline myopathy. Muscle histopathology showed increased fiber size variation and numerous nemaline bodies predominantly in small type 1 fibers. The patient was found to be compound heterozygous for two splice-site variants in intron 1a of TPM3: NM_152263.4:c.117+2_5delTAGG, deleting the donor splice site of intron 1a, and NM_152263.4:c.117 + 164 C>T, which activates an acceptor splice site preceding a non-coding exon in intron 1a. RNA sequencing revealed inclusion of intron 1a and the non-coding exon in the transcripts, resulting in early premature stop codons. Western blot using patient myoblasts revealed markedly reduced levels of the TPM3 protein. Novel biallelic splice-site variants were shown to markedly reduce TPM3 protein expression. The effects of the variants on splicing were readily revealed by RNA sequencing, demonstrating the power of the method.

Published
2023
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29. Respiratory muscle function in patients with nemaline myopathy

Author

Longziekten, Other research (not in main researchprogram), van Kleef, Esmee S B, van Doorn, Jeroen L M, Gaytant, Michael A, de Weerd, Willemien, Vosse, Bettine A H, Wallgren-Pettersson, Carina, van Engelen, Baziel G M, Ottenheijm, Coen A C, Voermans, Nicol C, Doorduin, Jonne, Longziekten, Other research (not in main researchprogram), van Kleef, Esmee S B, van Doorn, Jeroen L M, Gaytant, Michael A, de Weerd, Willemien, Vosse, Bettine A H, Wallgren-Pettersson, Carina, van Engelen, Baziel G M, Ottenheijm, Coen A C, Voermans, Nicol C, and Doorduin, Jonne

Published
2022

33. Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy

Author

de Winter, Josine M., Joureau, Barbara, Lee, Eun-Jeong, Kiss, Balázs, Yuen, Michaela, Gupta, Vandana A., Pappas, Christopher T., Gregorio, Carol C., Stienen, Ger J. M., Edvardson, Simon, Wallgren-Pettersson, Carina, Lehtokari, Vilma-Lotta, Pelin, Katarina, Malfatti, Edoardo, Romero, Norma B., van Engelen, Baziel G., Voermans, Nicol C., Donkervoort, Sandra, Bönnemann, C. G., Clarke, Nigel F., Beggs, Alan H., Granzier, Henk, and Ottenheijm, Coen A. C.

Published
2016
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36. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

Author

Lehtokari, Vilma-Lotta, Kiiski, Kirsi, Sandaradura, Sarah A., Laporte, Jocelyn, Repo, Pauliina, Frey, Jennifer A., Donner, Kati, Marttila, Minttu, Saunders, Carol, Barth, Peter G., den Dunnen, Johan T., Beggs, Alan H., Clarke, Nigel F., North, Kathryn N., Laing, Nigel G., Romero, Norma B., Winder, Thomas L., Pelin, Katarina, and Wallgren-Pettersson, Carina

Published
2014
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37. Congenital asymmetric distal myopathy with hemifacial weakness caused by a heterozygous large de novo mosaic deletion in nebulin

Author

Sagath, Lydia, primary, Lehtokari, Vilma-Lotta, additional, Välipakka, Salla, additional, Vihola, Anna, additional, Gardberg, Maria, additional, Hackman, Peter, additional, Pelin, Katarina, additional, Jokela, Manu, additional, Kiiski, Kirsi, additional, Udd, Bjarne, additional, and Wallgren-Pettersson, Carina, additional

Published
2021
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41. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Author

Yuen, Michaela, Sandaradura, Sarah A., Dowling, James J., Kostyukova, Alla S., Moroz, Natalia, Quinlan, Kate G., Lehtokari, Vilma-Lotta, Ravenscroft, Gianina, Todd, Emily J., Ceyhan-Birsoy, Ozge, Gokhin, David S., Maluenda, Jérome, Lek, Monkol, Nolent, Flora, Pappas, Christopher T., Novak, Stefanie M., DʼAmico, Adele, Malfatti, Edoardo, Thomas, Brett P., Gabriel, Stacey B., Gupta, Namrata, Daly, Mark J., Ilkovski, Biljana, Houweling, Peter J., Davidson, Ann E., Swanson, Lindsay C., Brownstein, Catherine A., Gupta, Vandana A., Medne, Livija, Shannon, Patrick, Martin, Nicole, Bick, David P., Flisberg, Anders, Holmberg, Eva, Van den Bergh, Peter, Lapunzina, Pablo, Waddell, Leigh B., Sloboda, Darcée D., Bertini, Enrico, Chitayat, David, Telfer, William R., Laquerrière, Annie, Gregorio, Carol C., Ottenheijm, Coen A.C., Bönnemann, Carsten G., Pelin, Katarina, Beggs, Alan H., Hayashi, Yukiko K., Romero, Norma B., Laing, Nigel G., Nishino, Ichizo, Wallgren-Pettersson, Carina, Melki, Judith, Fowler, Velia M., MacArthur, Daniel G., North, Kathryn N., and Clarke, Nigel F.

Published
2014
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42. Mutation Update and Genotype–Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

Author

Marttila, Minttu, Lehtokari, Vilma-Lotta, Marston, Steven, Nyman, Tuula A., Barnerias, Christine, Beggs, Alan H., Bertini, Enrico, Ceyhan-Birsoy, Özge, Cintas, Pascal, Gerard, Marion, Gilbert-Dussardier, Brigitte, Hogue, Jacob S., Longman, Cheryl, Eymard, Bruno, Frydman, Moshe, Kang, Peter B., Klinge, Lars, Kolski, Hanna, Lochmüller, Hans, Magy, Laurent, Manel, Véronique, Mayer, Michèle, Mercuri, Eugenio, North, Kathryn N., Peudenier-Robert, Sylviane, Pihko, Helena, Probst, Frank J., Reisin, Ricardo, Stewart, Willie, Taratuto, Ana Lia, de Visser, Marianne, Wilichowski, Ekkehard, Winer, John, Nowak, Kristen, Laing, Nigel G., Winder, Tom L., Monnier, Nicole, Clarke, Nigel F., Pelin, Katarina, Grönholm, Mikaela, and Wallgren-Pettersson, Carina

Published
2014
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45. Additional file 2 of Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Author

Laitila, Jenni, Elyshia McNamara, Wingate, Catherine, Goullee, Hayley, Ross, Jacob, Taylor, Rhonda, Pijl, Robbert Van Der, Griffiths, Lisa, Harries, Rachel, Ravenscroft, Gianina, Clayton, Joshua, Sewry, Caroline, Lawlor, Michael, Ottenheijm, Coen, Bakker, Anthony, Ochala, Julien, Laing, Nigel, Wallgren-Pettersson, Carina, Pelin, Katarina, and Nowak, Kristen

Abstract

Additional file 2. Summary of the whole muscle physiology results. a Individual muscle mass, maximum specific force, twitch specific force, maximal rate of force production (dF/dt), contraction time (time-to-peak), half-relaxation time. Unpaired t-test. b Force frequency, c eccentric damage, d eccentric peak stretch. Two-way ANOVA (Sidak’s multiple comparisons test). Data presented as mean +/− SEM; n = 8; *p

Published
2020
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46. Additional file 1 of Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Author

Laitila, Jenni, Elyshia McNamara, Wingate, Catherine, Goullee, Hayley, Ross, Jacob, Taylor, Rhonda, Pijl, Robbert Van Der, Griffiths, Lisa, Harries, Rachel, Ravenscroft, Gianina, Clayton, Joshua, Sewry, Caroline, Lawlor, Michael, Ottenheijm, Coen, Bakker, Anthony, Ochala, Julien, Laing, Nigel, Wallgren-Pettersson, Carina, Pelin, Katarina, and Nowak, Kristen

Abstract

Additional file 1. Fibre sizes and fibre-type proportions as numbers. 9-month-old female NebY2303H,Y935X mice, mean with standard deviation. Unpaired Mann-Whitney, n = 3, *p

Published
2020
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47. genetic diagnosis; limb-girdle weakness; neuromuscular disease; next-generation sequencing; targeted exome analysisweakness

Author

Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R., England, Eleina M., Laricchia, Kristen M., Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B., Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G., Akay, Ela, Alonso-Pérez, Jorge, Baets, Jonathan, Barisic, Nina, Bastian, Alexandra, Borell, Sabine, Chamova, Teodora, Claeys, Kristl, Colomer, Jaume, Coppens, Sandra, Deconinck, Nicolas, de Ridder, Willem, Díaz-Manera, Jordi, Domínguez-González, Cristina, Duncan, Alexis, Durmus, Hacer, Fahmy, Nagia A., Farrugia, Maria Elena, Fernández-Torrón, Roberto, Gonzalez- Quereda, Lidia, Haberlova, Jana, von der Hagen, Maja, Hahn, Andreas, Jakovčević, Antonia, Jerico Pascual, Ivonne, Kapetanovic, Solange, Kenina, Viktorija, Kirschner, Janbernd, Klein, Andrea, Kölbel, Heike, Kostera-Pruszczyk, Anna, Kulshrestha, Richa, Lähdetie, Jaana, Layegh, Mahsa, Longman, Cheryl, López de Munain, Adolfo, Loscher, Wolfgang, Lusakowska, Anna, Maddison, Paul, Magot, Armelle, Majumdar, Anirban, Martí, Pilar, Martínez Arroyo, Amaia, Mazanec, Radim, Mercier, Sandra, Mongini, Tiziana, Muelas, Nuria, Nascimento, Andrés, Nafissi, Shahriar, Omidi, Shirin, Ortez, Carlos, Paquay, Stéphanie, Pereon, Yann, Perić, Stojan, Ponzalino, Valentina, Rakočević Stojanović, Vidosava, Remiche, Gauthier, Rodríguez Sainz, Aida, Rudnik, Sabine, Sanchez Albisua, Iciar, Santos, Manuela, Schara, Ulrike, Shatillo, Andriy, Sertić, Jadranka, Stephani, Ulrich, Strang- Karlsson, Sonja, Sznajer, Yves, Tanev, Ani, Tournev, Ivailo, Van den Bergh, Peter, Van Parijs, Vinciane, Vílchez, Juan, Vill, Katharina, Vissing, John, Wallgren-Pettersson, Carina, Wanschitz, Julia, Willis, Tracey, Witting, Nanna, Zulaica, Miren, and Straub, Volker

Subjects
genetic diagnosis, limb-girdle weakness, neuromuscular disease, next-generation sequencing, targeted exome analysis
Abstract

Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers ; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases ; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes. .

Published
2020

48. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2

Author

Agrawal, Pankaj B., Greenleaf, Rebecca S., Tomczak, Kinga K., Lehtokari, Vilma-Lotta, Wallgren-Pettersson, Carina, Wallefeld, William, Laing, Nigel G., Darras, Basil T., Maciver, Sutherland K., Dormitzer, Philip R., and Beggs, Alan H.

Subjects
Muscle diseases -- Research, Muscle diseases -- Genetic aspects, Binding proteins -- Structure, Binding proteins -- Research, Muscle proteins -- Structure, Muscle proteins -- Research, Biological sciences
Abstract

The sixth thin-filament-related nemaline myopathy (NM) gene called CFL2 is identified encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy. It is found that cofilin-2 levels are significantly lower in the proband's muscle and the mutant protein is less soluble when expressed in Escherichia coli, suggesting that deficiency of cofilin-2 may result in reduced depolymerization of actin filaments.

Published
2007

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