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Centronuclear Myopathies Under Attack: a Plethora of Therapeutic Targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte

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Centronuclear Myopathies Under Attack: a Plethora of Therapeutic Targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte CORE Metadata, citation and similar papers at core.ac.uk Provided by Archive Ouverte en Sciences de l'Information et de la Communication Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte To cite this version: Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte. Centronuclear myopathies under attack: A plethora of therapeutic targets. Journal of Neuromuscular Diseases, IOS Press, 2018, 5, pp.387 - 406. 10.3233/JND-180309. hal-02438924 HAL Id: hal-02438924 https://hal.archives-ouvertes.fr/hal-02438924 Submitted on 14 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Neuromuscular Diseases 5 (2018) 387–406 387 DOI 10.3233/JND-180309 IOS Press Review Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaouta,b,c,d, Belinda S. Cowlinga,b,c,d,1 and Jocelyn Laportea,b,c,d,1,∗ aDepartment of Translational Medicine and Neurogenetics, Institut de G´en´etique et de Biologie Mol´eculaire et Cellulaire (IGBMC), Illkirch, France bInstitut National de la Sant´eetdelaRechercheM´edicale (INSERM), U1258, Illkirch, France cCentre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France dUniversit´e de Strasbourg, Illkirch, France Abstract. Centronuclear myopathies are a group of congenital myopathies characterized by severe muscle weakness, genetic heterogeneity, and defects in the structural organization of muscle fibers. Their names are derived from the central position of nuclei on biopsies, while they are at the fiber periphery under normal conditions. No specific therapy exists yet for these debilitating diseases. Mutations in the myotubularin phosphoinositides phosphatase, the GTPase dynamin 2, or amphiphysin 2 have been identified to cause respectively X-linked centronuclear myopathies (also called myotubular myopathy) or autosomal dominant and recessive forms. Mutations in additional genes, as RYR1, TTN, SPEG or CACNA1S, were linked to phenotypes that can overlap with centronuclear myopathies. Numerous animal models of centronuclear myopathies have been studied over the last 15 years, ranging from invertebrate to large mammalian models. Their characterization led to a partial understanding of the pathomechanisms of these diseases and allowed the recent validation of therapeutic proof-of-concepts. Here, we review the different therapeutic strategies that have been tested so far for centronuclear myopathies, some of which may be translated to patients. Keywords: Centronuclear myopathy, myotubular myopathy, myotubularin, amphiphysin, dynamin, gene therapy, autophagy, phosphoinositides, oligonucleotide, neuropathy BACKGROUND able advances have been made in understanding the physiopathology of CNM. A major step for- Centronuclear myopathies (CNM) are usually ward was the identification of the causative genetic defined as congenital myopathies with abnormally anomalies. MTM1 was the first identified gene positioned nuclei in the center of myofibers, in the mutated in the most severe form of CNM: X-linked absence of increased muscle regeneration commonly centronuclear or myotubular myopathy (XLMTM, observed in dystrophies [1]. Of note, CNM are linked CNMX, OMIM#310400) [3, 4]. This form is char- with a general disorganization of myofibers, with acterized clinically by a severe hypotonia and a abnormal positioning of different organelles, internal generalized muscle weakness often leading to res- membrane alterations and often myofibrillar mis- piratory failure and swallowing difficulties, and alignment and fiber shape defects. usually correlated with a poor prognosis [5–7]. In Since the first clinical and histopathological the vast majority of cases, loss-of-function muta- description of a 12-year-old affected boy with myotu- tions cause a strong decrease of the MTM1 protein bular myopathy in 1966 by Spiro et al. [2], remark- [8, 9], a phosphoinositides phosphatase implicated 1BSC and JL have equally contributed. in multiple cellular processes such as endosomal ∗Correspondence to: Jocelyn Laporte. Tel.: +33 0 388653412; trafficking [10–12], excitation-contraction coupling E-mail: [email protected]. [13, 14], intermediate filament organization [15], ISSN 2214-3599/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 388 H. Tasfaout et al. / Therapeutic targets for CNM neuromuscular junction (NMJ) structure [16, 17], pathogenesis and most translational research has satellite cell proliferation [18–20], and autophagy focused on these forms in the recent years. Weprovide [21, 22]. Female carriers can display a wide spectrum a summary of the different preclinical therapeutic of clinical and pathological involvement [23]. developments that have been explored for XLMTM The autosomal dominant (ADCNM) form is and autosomal forms of CNM. mainly caused by mutations in the dynamin 2 (DNM2) gene (ADCNM; OMIM#160150) [24]. The severity ranges from severely affected infant to mildly INCREASING OUR UNDERSTANDING affected adults [25]. In severe early onset cases, OF CNM THROUGH PHENOTYPING infants present with generalized muscle weakness, OF ANIMAL MODELS hypotonia with facial weakness in addition to oph- thalmoplegia [26], while in the late-onset milder Development of different animal models and their cases, young adult patients present with moderate characterization greatly accelerated the understand- muscle weakness leading to motor defects [27]. ing of the clinical, physiopathological and molecular DNM2 is a GTPase mechanoenzyme involved in aspects of CNM (Table 1). CNM, or their molecular endocytosis [28], exocytosis [29, 30], intracellular defects, have been modelled and studied in cultured membrane trafficking [31–33] and cytoskeletal orga- cells, yeast, drosophila, zebrafish, mice and dogs [51]. nization [34–36]. In vitro studies showed that CNM Moreover, they represent precious tools to test and mutations in DNM2 increase the GTPase activity and validate the different therapeutic approaches preclin- promote higher stability of polymers, suggesting a ically before embarking on clinical trials. gain-of-function mechanism in ADCNM [37, 38]. Three different mouse lines were developed to This is supported by the appearance of a CNM-like mimic XLMTM. The Mtm1 knockout (KO) mice with phenotype in mice over-expressing wildtype DNM2 a complete knockdown of the MTM1 protein present [39, 40]. a progressive myopathy starting from around week 3 Mutations in the BIN1 gene encoding amphiphysin with a shortened lifespan to around 7-8 weeks of age 2 have been reported in CNM patients linked to two [13, 61]. They exhibit similar features to XLMTM modes of inheritance: autosomal recessive [41, 42] patients, including muscle atrophy and severe weak- and autosomal dominant [43] (OMIM#255200). A ness, and muscle biopsies feature small rounded large variability in severity is observed in affected fibers with a high frequency of abnormal localization patients, however the main consistent presentation of nuclei and disorganized mitochondrial distri- is muscular atrophy with diffuse muscle weakness bution. Ultrastructural analysis revealed dramatic [1, 44, 45]. BIN1 generates and maintains membrane decrease of normal triads [13], membrane invagina- curvature and tubulation through the BAR domain tion implicated in excitation coupling machinery, as [46], while the SH3 domain is involved in recruitment well as sarcomere disorganization and enlargement of of endocytotic proteins such as DNM2 [41, 47, 48]. neuromuscular junctions [17, 62]. Additional stud- Recessive mutations decrease the membrane tubu- ies have shown defects in mitochondrial dynamics, lation properties of BIN1 [41]. Of note, BIN1 also desmin aggregation and alteration in autophagy and binds phosphoinositides and MTM1 [46, 47, 49, 50], ubiquitin-proteasome pathways [15, 63]. A knock-in suggesting a common pathway linking MTM1, BIN1 (KI) mouse carrying the R69C mutation was gen- and DNM2 [51]. erated to mimic a mutation identified in XLMTM The incidence of CNM is about 1-2 per 100,000 patients with a mild phenotype [64]. The R69C muta- births, comprised of mutations in MTM1 (∼50%), tion results in exon 4 skipping leading to premature DNM2 (∼15%) or BIN1 (∼3%), other implicated termination of myotubularin translation. However, genes (∼12%), or CNM with unknown genetic basis some full-length MTM1 protein was still expressed in (∼20%) [52]. Mutations in Ryanodine receptor 1 this model, resulting in a milder phenotype compared (RYR1) [53, 54], Titin (TTN) [55], SPEG [56], to Mtm1KO mice, with a median lifespan of 66 weeks. DHPR (CACNA1S) [57], ZAK [58], and potentially This observation suggests that expression of a small myotubularin-related protein 14 (MTMR14) [59] and amount of MTM1 may have significant clinical bene- CCDC78 [60], have been reported to cause congenital fits in XLMTM. A third mouse model, the Mtm1gt/y , myopathies with a CNM-like
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