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ColVI myopathies: where do we stand, where do we go?

ColVI myopathies: where do we stand, where do we go? Collagen VI myopathies, caused by mutations in the genes encoding collagen type VI (ColVI), represent a clinical continuum with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) at each end of the spectrum, and less well-defined intermediate phenotypes in between. ColVI myopathies also share common features with other disorders associated with prominent muscle contractures, making differential diagnosis difficult. This group of disorders, under-recognized for a long time, has aroused much interest over the past decade, with important advances made in understanding its molecular pathogenesis. Indeed, numerous mutations have now been reported in the COL6A1, COL6A2 and COL6A3 genes, a large proportion of which are de novo and exert dominant-negative effects. Genotype-phenotype correlations have also started to emerge, which reflect the various pathogenic mechanisms at play in these disorders: dominant de novo exon splicing that enables the synthesis and secretion of mutant tetramers and homozygous nonsense mutations that lead to premature termination of translation and complete loss of function are associated with early-onset, severe phenotypes. In this review, we present the current state of diagnosis and research in the field of ColVI myopathies. The past decade has provided significant advances, with the identification of altered cellular functions in animal models of ColVI myopathies and in patient samples. In particular, mitochondrial dysfunction and a defect in the autophagic clearance system of skeletal muscle have recently been reported, thereby opening potential therapeutic avenues. Review ColVI is a heterotrimeric molecule composed of three Collagen VI: an important component of connective individual a(VI) chains that display a similar structure, tissues with a triple helical domain characterized by the repeti- Collagens are major constituents of the extracellular tion of the Gly-X-Y amino acid sequence, flanked by matrix (ECM), and are found in most connective tissues. globular domains homologous to von Willebrand factor They provide structural and mechanical stability to tis- A domains [16,17]. In addition to the well-known a1 sues, but they also play crucial roles in cell-ECM inter- (VI), a2(VI) and a3(VI) chains encoded in human by actions through various receptors [1]. In particular, the COL6A1, COL6A2 (located head-to-tail on chromo- collagen type VI (ColVI), an important component of some 21q22.3), and COL6A3 (on chromosome 2q37) skeletal muscle ECM, is involved in maintaining tissue genes [18], three novel chains, a4(VI), a5(VI) and a6 integrity by providing a structural link between different (VI), have recently been identified [19,20]. These chains constituents of connective-tissue basement membranes have high structural homology to the a3(VI) chain. In humans, the COL6A4, COL6A5 and COL6A6 genes are (for example, collagen types I and IV, biglycan, and dec- orin) and cells [2-15] (Figure 1). In addition to its struc- all located on chromosome 3q22.1, with the COL6A4 tural role, ColVI supports adhesion, spreading and gene being split by a chromosome break and thus not migration of cells, and cell survival, as discussed later in coding for a protein [19-21]. The murine orthologs of this review. these genes are organized in tandem on chromosome 9 (Col6a4, Col6a5 and Col6a6) and encode the a4(VI), a5 (VI) and a6(VI) chains. The expression pattern of the * Correspondence: v.allamand@institut-myologie.org three novel chains differs between mice and humans, Inserm, U974, Paris, France and also between fetal and adult tissues [19,20]. Full list of author information is available at the end of the article © 2011 Allamand et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Allamand et al. Skeletal Muscle 2011, 1:30 Page 2 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 1 Schematic representation of the collagen type VI (ColVI) intracellular assembly process, and interactions with skeletal muscle extracellular matrix (ECM) components. Individual a(VI) chains fold through their triple helical domains to form monomers (1:1:1 ratio) in the endoplasmic reticulum (ER), which further align in an anti-parallel manner as dimers and tetramers that are stabilized by disulfide bonds between cysteine residues (S = S links). Post-translational modifications (indicated in orange) take place in the ER and Golgi, followed by secretion of tetramers that align non-covalently end to end, to form beaded microfibrils in the ECM. ColVI interacts with collagenous and non- collagenous components of the basal lamina and interstitial matrix surrounding muscle fibers. Allamand et al. Skeletal Muscle 2011, 1:30 Page 3 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Importantly, in the context of ColVI myopathies, the a6 described separately but now recognized as the extreme (VI) chain is the only one expressed at high levels in ends of a continuous clinical spectrum [38,39] (Figure human skeletal muscle, at higher levels in fetal than 2). The severe endpoint of this spectrum corresponds to adult tissue [19]. In skin, a detailed analysis of the Ullrich congenital muscular dystrophy (UCMD, OMIM expression of the human a5(VI) and a6(VI) chains 254090; http://www.ncbi.nlm.nih.gov/omim), described revealed that both chains are expressed, albeit differ- in 1930 as ‘congenital atonic-sclerotic muscular dystro- ently, and that they are variably altered in tissues from phy’, emphasizing its early onset and the presence of patients with mutations in the COL6A1, COL6A2 and proximal joint contractures associated with a striking COL6A3 genes [22]. Interestingly, the COL6A5 gene had distal hyperlaxity [40,41]. Orthopedic deformities (joint previously been reported as associated with atopic der- contractures, scoliosis) and respiratory impairment with matitis under the name COL29A1 [23], but this associa- diaphragmatic failure generally develop within the first tion has recently been questioned [24,25]. The knee decade of life, and may be life-threatening. Arrest of osteoarthritis susceptibility locus DVWA was shown to motor milestones with no acquisition of walking ability correspond to the 5’ part of the split COL6A4 gene [21]. is seen in a subset of patients, but most children are Although largely ubiquitous, the expression of ColVI able to walk, and show later progression of muscle seems to be finely regulated in different cell types and weakness with loss of ambulation around 10 years of tissues, as shown for the murine Col6a1 gene. The iden- age, and a requirement for mechanical ventilation in late tification of a transcriptional enhancer located in the 5’- childhood or young adulthood [42,43]. flanking sequence of the gene points to a collaborative At the other end of the spectrum is the milder form crosstalk between myogenic and mesenchymal/endomy- Bethlem myopathy (BM, OMIM 158810), described in sial cells, enabling transcription of ColV in muscle con- 1976, which begins in the first or second decade, nective tissue [26-28]. although a neonatal history may be recognized, charac- The a1(VI), a2(VI) and a3(VI) chains assemble intra- terized by early contractures of finger flexors, wrist, cellularly as monomers (1:1:1 ratio), from their C-term- elbows and ankles [44,45]. Respiratory failure and distal inal ends, and subsequently form dimers (two anti- hyperlaxity are usually absent or are milder than in parallel, overlapping monomers) and tetramers (four UCMD, although the latter may not be so uncommon monomers) that are stabilized by disulfide bonds in very young children withBM. Thecourseisusually between cysteine residues of the three chains [29-34]. slow, with most of the patients remaining ambulatory. ColVI chains are subjected to extensive post-transla- However, progression of muscle weakness occurs often tional modifications such as hydroxylation of lysine and in the fifth decade, resulting in about 50% of patients proline residues [35], and glycosylation of hydroxyly- requiring walking aids or a wheelchair [46]. Intermediate sines, which have been shown to be essential for the tet- phenotypes have been described, and named ‘mild ramerization and further secretion of ColVI [36,37]. UCMD’ or ‘severe BM’, thereby reinforcing the notion Upon secretion, tetramers are further aligned end to of clinical overlap between Ullrich and Bethlem pheno- end as microfibrils in the extracellular space, with a types [38,39]. characteristic beaded appearance [33] (Figure 1). To Skin features such as follicular hyperkeratosis and date, somewhat contradictory results have been obtained hypertrophic scars or keloid formation are common regarding the possible assembly of the newly character- [38,39,42,43,47-49]. Other common findings include ized a(VI) polypeptides with the a1(VI), a2(VI) chains. normal cognitive abilities, normal or only slightly raised In transfection experiments, only a4(VI) appeared to serum creatine kinase (CK) levels, and absence of car- have this ability [19], whereas in mouse muscle, all three diac phenotype. Two other conditions that fall within were reported to do so [20]. Whether and how these the spectrum of ColVI myopathies have been documen- additional chains may fit in the pathogenesis of ColVI ted: autosomal dominant limb-girdle muscular dystro- myopathies remains unresolved to date, and needs to be phy (LGMD) (in three families) and, more recently, addressed more comprehensively. To date, in our cohort autosomal recessive myosclerosis myopathy (OMIM of patients, no pathogenic mutations have been found 255600) (in one family) [50,51]. by sequencing of the COL6A5 and COL6A6 genes in The prevalences of UCMD and BM in northern Eng- patients without mutations in the COL6A1-3 genes (V. land has recently been reported as 0.13 and 0.77 per Allamand, data not shown). 100,000, respectively, amounting collectively to 0.9 per 100,000 [52]. UCMD seems to be the second most com- Clinical phenotypes of collagen VI myopathies mon type of congenital muscular dystrophy (CMD) in The etiological definition of ColVI myopathies as a spe- Europe (behind laminin a2 chain deficiency; OMIM 607855) and also in Japan (behind Fukuyama congenital cific condition has evolved over the years with the blur- muscular dystrophy; OMIM 253800, [53]) and Australia ring of boundaries between two disorders, initially Allamand et al. Skeletal Muscle 2011, 1:30 Page 4 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 2 Clinical spectrum, associated spine deformation and muscle MRI in collagen type VI (ColVI) myopathies. (A),Early severe phenotypes, corresponding to classic Ullrich congenital muscular dystrophy (UCMD), (B) intermediate forms seen in children or adults and (C) less severe, classic Bethlem myopathy (BM) forms constitute the overlapping clinical presentations of ColVI myopathies. (D) Radiography showing the evolution of spine deformation in a patient presenting with a classic early-onset UCMD phenotype. T1 transverse section of Bethlem myopathy upper limb girdle (E) and (F) thighs. Note the fatty infiltration, which appears as hyperintense area on T1-weighted images, located around the triceps brachialis muscles in (E) and along the fascia of vastus lateralis and vastus medialis muscles in (F) (yellow arrows). (G) The concentric fatty involvement of the thigh muscles is also seen on whole body MRI. (Images courtesy of Drs Susana Quijano-Roy and Tanya Stojkovic). (behind a-dystroglycan glycosylation defects; [54]). In [55-57]. Imaging techniques, such as computed the cohort from northern England, BM emerges as the tomography or magnetic resonance imaging (MRI) of fourth most common myopathy behind myotonic dys- muscle, are now recognized as very helpful in the diag- trophy (OMIM 160900), facio-scapulo-humeral muscu- nostic approach of muscle disease, because there are lar dystrophy (OMIM 158900) and Duchenne/Becker specific patterns of muscle involvement in each of muscular dystrophy (OMIM 310200 and 300376) [52]. these contractile myopathies as reported for EDMD with LMNA mutations [58], muscular dystrophies with Differential diagnosis of ColVI-related myopathies rigidity of the spine [59], and ColVI myopathies With the most prominent clinical presentation of [58,60,61]. From these studies, the typical pattern of ColVI myopathies being muscle weakness and contrac- muscle involvement in ColVI myopathies is now con- tures, associated with variable degrees of hyperlaxity, sidered to be constituted by a diffuse, concentric hypo- an important difficulty lies in defining boundaries and density of the thigh muscles with relative sparing of contiguities, with the possible differential diagnosis the sartorius, gracilis and adductor longus muscles. including congenital myopathies, Emery-Dreifuss mus- The vasti muscles are the most affected muscles. In cular dystrophy (EDMD; OMIM 181350), LGMD, rigid addition, a peculiar centralareaofabnormalsignalis spine muscular dystrophies, and other diseases of con- seen within the rectus femoris, initially referred to as a nective tissues such as Ehlers-Danlos syndrome ‘central shadow’ [62]. Allamand et al. Skeletal Muscle 2011, 1:30 Page 5 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 In the context of the differential diagnosis, the absence in the COL6A1 and COL6A2 genes. The most common of raised CK levels, the lack of a cardiac phenotype, and types of mutations are point mutations, and mutations the presence of a specific MRI pattern are strongly sug- leading to premature termination codons (PTCs) and gestive of a ColVI myopathy. exon skipping (Figure 4). Among the former, missense changes affecting glycine residues in the triple helical Molecular diagnosis and genetics domains of the corresponding proteins are the most common, and are often dominant de novo. Because In light of the clinical variability and the overlapping these changes affect crucial amino acids within the col- presentation with other muscular disorders, a definite lagenous domains, they hamper triple-helix formation diagnosis can only be made after the identification of pathogenic mutations in one of the COL6A genes, [74-77]. Splice mutations resulting in in-frame exon which to date are restricted to COL6A1, COL6A2 and skipping are generally dominant de novo mutations, and COL6A3. However, the large size (106 coding exons in exons 16 of COL6A3 and 14 of COL6A1 seem to be total corresponding to 150 kb of genomic DNA) of preferentially affected, leading to UCMD or BM pheno- these genes makes routine molecular diagnostics costly types, respectively [53,75,78-83]. Nonsense mutations and time-consuming. The road to this ‘holy grail’ of and small deletions or insertions inducing PTCs within diagnosis is thus often lengthy and full of pitfalls, and the coding frame are mostly inherited as recessive muta- relies on a combination of clinical, biochemical and tions, and lead to loss of function of the protein molecular findings. [42,53,68,75,76,79-92]. These mutations are responsible Historically, muscle biopsies were the routine and pri- for most UCMD phenotypes. Nevertheless, it should be mary step undertaken for diagnostic purposes, and dou- noted that genotype-phenotype correlations are very dif- ble immunostaining with a basement-membrane marker ficult to identify. enabled recognition of ColVI deficiency in patients with It has recently been shown that all types of mutations UCMD [63], but not in patients with BM. The current alter transcript levels, and that in the case of PTC-bear- diagnostic method of determining ColVI involvement is ing transcripts, which are specifically degraded via the primarily based on immunocytochemistry of cultured nonsense-mediated mRNA decay (NMD [93,94]) path- skin fibroblasts, but this analysis is only available in a way, quantification of the three COL6A mRNAs is a limited number of laboratories to date. A number of helpful tool to pinpoint the mutated gene, thereby facili- antibodies recognizing human ColVI are now commer- tating these cumbersome molecular analyses [42]. The NMD-induced degradation of PTC-bearing transcripts cially available and may be used for such techniques; in may also, at least in part, explain why the parents of particular, the refined protocol proposed by Hicks et al. [64], using a polyclonal antibody raised against mature patients with UCMD who themselves harbor recessive ColVI from human placenta, has better sensitivity, espe- mutations are asymptomatic; their heterozygous status cially in fibroblast cultures from patients with BM sustains the expression of 50% of the ‘normal’ protein, (Figure 3). The absence or alteration of ColVI secretion thereby leading to a ‘functional loss of heterozygosity’. in cultured fibroblasts, associated with clinical symptoms The study by Briñas and collaborators also provided compatible with a diagnosis of ColVI myopathy, cer- some genotype-phenotype correlations in a cohort of tainly warrants further genetic analysis. patients with early-onset ColVI myopathy, showing that Over the past decade, the development of genetic stu- recessive mutations leading to PTC were associated with dies has demonstrated the heterogeneity and complexity severe phenotypes [42]. Genetic studies are further com- of the molecular mechanisms at play in ColVI myopa- plicated by a possibly variable penetrance as reported by thies. An autosomal recessive pattern of inheritance was Peat et al. [89]. initially thought to be involved in UCMD, and linkage Finally, the highly polymorphic nature of the COL6A analysis led to the identification of mutations in the genes makes it difficult to definitely assign pathogenicity COL6A2 and COL6A3 genes [65-67]. However, numer- to some variants, especially missense ones that do not ous dominant de novo mutations have now been shown affect glycine residues within the triple-helix domains of to be involved, accounting for more than 50% of the the proteins. In addition, these ‘polymorphisms’ may mutations causing UCMD [38,39,42,68]. Similarly, auto- very well play a role in the extreme clinical variability of somal dominant mutations were first identified in the these conditions, particularly in patients carrying identi- COL6A1 and COL6A2 genes in families with BM, sug- cal mutations but presenting with variable severity. gesting that BM was mostly familial and inherited as an The types of mutations identified also reflect the autosomal dominant disease [69], although rare de novo methods used in laboratories performing these analyses mutations and autosomal recessive mutations have now (for example, sequencing of genomic DNA or of the been reported [70-73]. To date, over 200 mutations coding sequences on cDNA), but the emergence of have been identified in these genes, mostly distributed high-throughput methods (arrays) is likely to allow the Allamand et al. Skeletal Muscle 2011, 1:30 Page 6 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 3 Collagen type VI (ColVI) expression study in cultured skin fibroblasts. (A) Representative images obtained using the protocol from [67] in which ColVI (red) is labeled with monoclonal antibody MAB1944 (Chemicon (now Millipore), Billerica, MA, USA) and perlecan (green) with monoclonal antibody MAB1948 (Chemicon). Note that ColVI expression appeared clearly altered in a patient with an early severe (ES) form and less so in patients with intermediate (Int) or Bethlem myopathy (BM) forms, compared with control fibroblasts (Cont). (B) Using the protocol of Hicks et al. [64], which detects ColVI (red) with polyclonal antibody Ab6588 (Abcam, Cambridge, UK) and fibronectin (green) with monoclonal antibody F15 (Sigma Chemical Co., St Louis, MO, USA), the sensitivity of the method is increased, and defective ColVI secretion could be detected in all patients’ samples. Insets indicate nuclei, labeled using DAPI. Bars are 50 μm. (Images courtesy of Corine Gartioux and Valérie Allamand). identification of as yet unknown or under-recognized proven central to understanding the cellular pathways pathogenic mechanisms, such as large gene rearrange- involved in these diseases. Homozygous animals were ments, or promoter or deep intronic mutations, as reported to develop a mild myopathic phenotype, and recently illustrated in two reports [95,96]. were initially described as a model of BM [97]. Interest- ingly, the diaphragm was the most affected muscle, with Animal models and pathophysiology signs of necrosis evidenced by uptake of Evan’s blue dye Limited access to muscle biopsies hinders extensive [97]. Subsequently, a latent mitochondrial dysfunction investigations of the specific cellular mechanisms leading accompanied by ultrastructural alterations of mitochon- to the development of the muscle pathology, and in dria and the sarcoplasmic reticulum, resulting in sponta- neous apoptosis, was found in about one-third of muscle vitro/ex vivo cellular systems only partially reproduce the complexity of the tissue. The development of the fibers [98]. Reduced contractile strength of the dia- first animal model of ColVI deficiency in 1998, engi- phragm and other muscle groups was also reported in -/- neered by invalidating the Col6a1 gene in mice, has Col6a1 mice in this initial study [98]. The maximal Allamand et al. Skeletal Muscle 2011, 1:30 Page 7 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 4 Repartition of the various types of mutations identified in the COL6A1, COL6A2 and COL6A3 genes. This schematic reflects, to the best of our ability, the distribution of 258 allelic mutations (98 on COL6A1, 113 on COL6A2 and 47 on COL6A3). Dominant de novo mutations represent 67% of the missense mutations, affecting glycine residues in the TH domains (Gly in TH), 57% of small deletions (< 5 amino acids) and 44% of splice-site mutations leading to in-frame exon skipping, whereas 97% of mutations leading to premature termination codons (PTCs) are familial (recessive or dominant). isometric tension generated by ColVI-deficient skinned showed that patients-derived skin fibroblasts behave dif- fibers from gastrocnemius was found to be reduced in a ferently from myoblasts in that respect, and also ques- recent report; however, using a protocol of eccentric tioned the specificity of this mitochondrial dysfunction contractions in vivo, no muscle force drop was found, [102], warranting further studies on the matter. indicating that the lack of ColVI does not impair myofi- A role for cell survival had previously been proposed brillar function [99]. Importantly, mitochondrial dys- for ColVI because it was shown to prevent anti-a1 function was also reported in cultured muscle cells from integrin-mediated apoptosis and trigger the downregula- patients and could be reversed by cyclosporin (Cs)A, an tion of bax, a pro-apoptotic molecule [103,104]. immunosuppressive drug that prevents the opening of Recently, a study of the autophagic process in muscles the mitochondrial permeability transition pore through of Col6a1 knockout mice revealed that autophagy was binding to cyclophilin D, and also inhibits the phospha- not induced efficiently [105]. The ensuing defective tase calcineurin [100,101]. Another in vitro study autophagy provides the link between the previously Allamand et al. Skeletal Muscle 2011, 1:30 Page 8 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 5 Current pathological hypotheses and therapeutic targets. The currently known cascade of main events leading to myofiber degeneration in ColVI-deficient skeletal muscle is shown. Mitochondrial dysfunction (due in part to the defective permeability transition pore (PTP) opening) triggers an energetic imbalance with the increased levels of phosphorylated adenosine monophosphate-activated protein kinase 2+ (p-AMPK), Ca overload and the production of reactive oxygen species (ROS). Lack of autophagy induction exacerbates the cellular dysfunction because defective mitochondria and proteins (such as p62 aggregates) are not cleared from the cytoplasm. Together, these defects lead to increased apoptosis. Potential therapeutic interventions are indicated in green. Allamand et al. Skeletal Muscle 2011, 1:30 Page 9 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 described mitochondrial dysfunction and myofiber a chemical derivative of (-)-deprenyl, which was shown degeneration, as abnormal organelles and molecules to reduce GAPDH-Siah1-mediated apoptosis in a mouse cannot be efficiently cleared from the cell. This study model of laminin a2 chain deficiency [114]. further showed that the forced induction of autophagy, Itshouldbe notedthattranslatingsome of this either by dietary restriction or by treatment with rapa- research from animal models to patients represents a mycin or CsA, ameliorated the phenotype of the challenging task, particularly because, to date, these -/- Col6a1 mice (Figure 5). A similar alteration of autop- drugs have not been approved for use in children, the hagy was also detected in muscle biopsies derived from patient population with the most severe forms of ColVI nine patients with UCMD or BM [105]. These data thus myopathies. In addition, there is concern about these provide a basis for novel therapeutic targets to promote therapeutic approaches because of the pleiotropic, and the elimination of defective organelles in ColVI-deficient potentially harmful, consequences of anti-apoptotic and/ skeletal muscle. or pro-autophagy treatments. Furthermore, such Morpholino-mediated knock-down of the col6a1 and approaches aiming at modulating downstream pathways col6a3 genes in zebrafish embryos showed that collagen would not address the primary defect in these disorders, VI deficiency significantly impairs muscle development that is, lack of ColVI in the connective tissue, and and function [106]. Increased apoptosis, partially pre- would thus need to be continually administered. For the vented by CsA treatment, was also described in the zeb- sake of discussion, several alternative, and not necessa- rafish morphants [106]. As in other instances, rily exclusive, therapeutic avenues that would sustain re- perturbation of muscle components leads to a more expression of ColVI may be envisioned. These severe phenotype in zebrafish than in mouse models, approaches may consist of gene-based therapies, such as which may in part be due to intrinsic differences in vector delivery of ColVI-coding sequence, and antisense muscle development in these species, especially in terms inhibition of mutant transcripts exerting dominant- of timing. Zebrafish models have emerged as major in negative effects [96]. Additionally, as nonsense muta- vivo models of neuromuscular disorders, and seem to be tions leading to PTCs are often associated with early- particularly well suited for whole-organism screens for onset, severe phenotypes [42], pharmacological potential pharmacological treatments, as recently illu- approaches aiming to ‘force’ translation of PTCs (a phe- strated in zebrafish models of Duchenne muscular dys- nomenon known as ‘translational readthrough’ [115]) trophy [107]. may prove beneficial for a subset of patients carrying these types of mutations. However, the complex assem- Therapeutic intervention bly process and regulation of ColVI may prove challen- ging and may limit the realistic options to be To date, no curative treatment exists for these disorders, and most patients rely on supportive treatment of symp- investigated. toms, usually involving orthopedic (spinal deformations, contractures) and respiratory complications [108]. Conclusions The unveiling of mitochondrial dysfunction led to an The past decade of research on neuromuscular disorders open pilot trial in five patients with UCMD or BM trea- has proven very exciting, and has seen ColVI myopa- ted orally with CsA for 1 month [109]. This study thies emerge as an important set of disorders, rather reported normalization of the mitochondrial dysfunction under-recognized until recently. Many challenges remain and decrease of apoptosis of muscle cells following this despite the tremendous advances in the understanding short-term treatment [110,111]. Longer treatment (up to of their genetic, biochemical and pathophysiological 2 years) had some beneficial effect on muscle function bases. It is hoped that the decade(s) to come will see the in these patients but did not prevent progression of the development of safe and efficient therapies for these dis- disease in the children [38]. Debio-025 (D-MeAla3Et- orders. Consequently, as for other rare diseases, the Val4-cyclosporin; DebioPharm) prevents the inappropri- scientific community, and patient organizations, and ate opening of the mitochondrial permeability transition patients and their families have become increasingly pore (PTP) without interfering with calcineurin [112], aware of the need for databases, both clinical and and was shown to restore mitochondrial function in cul- genetic, to facilitate recruitment of patients for upcom- -/- tured muscle cells of patients [100] and in Col6a1 ing clinical trials. mice [113]. Debio-025 is currently being tested in a phase II clinical trial in patients with chronic hepatitis List of abbreviations used C. Another anti-apoptotic pharmacological agent that is BM: Bethlem myopathy; ColVI: collagen type VI; COL6A: gene(s) encoding the being investigated in the context of ColVI myopathies is alpha chain(s) of collagen VI; CsA: cyclosporin A; DAPI: 4’,6-diamidino-2- phenylindole; EDMD: Emery-Dreifuss muscular dystrophy; EDS: Ehlers-Danlos Omigapil (N-(dibenz(b, f)oxepin-10-ylmethyl)-N-methyl- syndrome; LMNA: gene encoding lamin A/C; MDC1A: congenital muscular N-prop-2-ynylamine maleate; Santhera Pharmaceuticals), Allamand et al. Skeletal Muscle 2011, 1:30 Page 10 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 dystrophy with laminin α2 chain deficiency; PTP: permeability transition pore; Received: 24 March 2011 Accepted: 23 September 2011 MRI: magnetic resonance imaging; PTC: premature termination codon; ROS: Published: 23 September 2011 reactive oxygen species; SEPN1: gene encoding selenoprotein N; TNXB: gene encoding tenascin-X; UCMD: Ullrich congenital muscular dystrophy References 1. Leitinger B, Hohenester E: Mammalian collagen receptors. Matrix Biol 2007, Acknowledgements 26:146-155. We thank Corine Gartioux and Céline Ledeuil for excellent technical skills. 2. Bidanset D, Guidry C, Rosenberg L, Choi H, Timpl R, Hook M: Binding of This study was funded by the Institut National de la Santé et de la the proteoglycan decorin to collagen type VI. J Biol Chem 1992, Recherche Médicale (Inserm), Association Française contre les Myopathies 267:5250-5256. 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All authors read Biol 1992, 118:979-990. and approved the final manuscript. 9. Kuo H-J, Maslen CL, Keene DR, Glanville RW: Type VI collagen anchors endothelial basement membranes by interacting with Type IV collagen. Authors’ information J Biol Chem 1997, 272:26522-26529. Valérie Allamand holds a PhD in Human Genetics, and currently leads a 10. McDevitt CA, Marcelino J, Tucker L: Interaction of intact type VI collagen group focusing on ColVI myopathies in the research unit directed by with hyaluronan. FEBS Letters 1991, 294:167-170. Thomas Voit. In 2009, she co-organized, with Drs Kate Bushby and Luciano 11. Pfaff M, Aumailley M, Specks U, Knolle J, Zerwes HG, Timpl R: Integrin and Merlini, the 166th ENMC International Workshop on Collagen Type VI- Arg-Gly-Asp dependence of cell adhesion to the native and unfolded Related Myopathies (22-24 May 2009, Naarden, The Netherlands). She is the triple helix of collagen type VI. Exp Cell Res 1993, 206:167-176. genetic curator of the UMD-COL6 databases, developed in the context of 12. Specks U, Mayer U, Nischt R, Spissinger T, Mann K, Timpl R, Engel J, the Treat-NMD European network of excellence. Chu ML: Structure of recombinant N-terminal globule of type VI collagen Laura Briñas obtained her PhD in Molecular Biology. She joined the Institut alpha 3 chain and its binding to heparin and hyaluronan. Embo J 1992, de Myologie in September 2006 as a post-doctoral fellow, and has been 11:4281-4290. involved in the molecular analysis of mutations in the genes encoding 13. Takahashi T, Cho HI, Kublin CL, Cintron C: Keratan sulfate and dermatan collagen VI and the dissection of their cellular consequences. sulfate proteoglycans associate with type VI collagen in fetal rabbit Susana Quijano-Roy is a child neurologist with previous medical training in cornea. J Histochem Cytochem 1993, 41:1447-1457. La Paz Hospital (Madrid, Spain) and Boston Children’s Hospital (USA). She has 14. Tillet E, Ruggiero F, Nishiyama A, Stallcup WB: The membrane-spanning held a clinical practice since 2001 at Garches Neuromuscular Reference proteoglycan NG2 binds to collagens V and VI through the central Center (GNMH), and leads the pediatric EMG laboratory at Necker Enfants nonglobular domain of its core protein. J Biol Chem 1997, Hospital, Paris. She obtained her PhD in 2004 with a study on congenital 272:10769-10776. muscular dystrophies (CMDs). She is part or the international expert group 15. Wiberg C, Klatt AR, Wagener R, Paulsson M, Bateman JF, Heinegard D, that is currently defining diagnosis, standards of care and natural history of Morgelin M: Complexes of matrilin-1 and biglycan or decorin connect CMDs and establishing outcome measures for future therapeutic trials. collagen VI microfibrils to both collagen II and aggrecan. J Biol Chem Tanya Stojkovic is a medical doctor, specialized in neurophysiology and 2003, 278:37698-37704. neuromuscular disorders. She has worked in the neuromuscular clinical unit 16. Chu ML, Pan TC, Conway D, Kuo HJ, Glanville RW, Timpl R, Mann K, directed by Professor Eymard since 2006 (Pitié-Salpêtière, Institut de Deutzmann R: Sequence analysis of alpha 1(VI) and alpha 2(VI) chains of Myologie, Paris, France). She is involved, as a clinician, in the diagnosis of human type VI collagen reveals internal triplication of globular domains neuromuscular disorders. She has a special interest in ColVI-related similar to the A domains of von Willebrand factor and two alpha 2(VI) myopathies. chain variants that differ in the carboxy terminus. EMBO J 1989, Pascale Richard holds a PharmD, Graduation from Medical Biologist and a 8:1939-1946. PhD in molecular genetics. She is head of the ‘Functional Unit of Molecular 17. 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Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P: Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 2010, 16:1313-1320. 106. Telfer WR, Busta AS, Bonnemann CG, Feldman EL, Dowling JJ: Zebrafish models of collagen VI-related myopathies. Hum Mol Genet 2010, 19:2433-2444. 107. Kawahara G, Karpf JA, Myers JA, Alexander MS, Guyon JR, Kunkel LM: Drug screening in a zebrafish model of Duchenne muscular dystrophy. Proc Natl Acad Sci USA 2011, 108:5331-5336. 108. Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, et al: Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol 2010, 25:1559-1581. Submit your next manuscript to BioMed Central 109. Merlini L, Angelin A, Tiepolo T, Braghetta P, Sabatelli P, Zamparelli A, and take full advantage of: Ferlini A, Maraldi NM, Bonaldo P, Bernardi P: Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with • Convenient online submission collagen VI myopathies. Proc Natl Acad Sci USA 2008, 105:5225-5229. 110. Maraldi NM, Sabatelli P, Columbaro M, Zamparelli A, Manzoli FA, Bernardi P, • Thorough peer review Bonaldo P, Merlini L: Collagen VI myopathies: From the animal model to • No space constraints or color figure charges the clinical trial. Advances in Enzyme Regulation 2009, 49:197-211. • Immediate publication on acceptance 111. Merlini L, Bernardi P: Therapy of collagen VI-related myopathies (Bethlem and Ullrich). Neurotherapeutics 2008, 5:613-618. • Inclusion in PubMed, CAS, Scopus and Google Scholar 112. Hansson MJ, Mattiasson G, Månsson R, Karlsson J, Keep MF, Waldmeier P, • Research which is freely available for redistribution Ruegg UT, Dumont J-M, Besseghir K, Elmér E: The Nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Skeletal Muscle Springer Journals

ColVI myopathies: where do we stand, where do we go?

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Copyright © 2011 by Allamand et al; licensee BioMed Central Ltd.
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Life Sciences; Cell Biology; Developmental Biology; Biochemistry, general; Systems Biology; Biotechnology
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Abstract

Collagen VI myopathies, caused by mutations in the genes encoding collagen type VI (ColVI), represent a clinical continuum with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) at each end of the spectrum, and less well-defined intermediate phenotypes in between. ColVI myopathies also share common features with other disorders associated with prominent muscle contractures, making differential diagnosis difficult. This group of disorders, under-recognized for a long time, has aroused much interest over the past decade, with important advances made in understanding its molecular pathogenesis. Indeed, numerous mutations have now been reported in the COL6A1, COL6A2 and COL6A3 genes, a large proportion of which are de novo and exert dominant-negative effects. Genotype-phenotype correlations have also started to emerge, which reflect the various pathogenic mechanisms at play in these disorders: dominant de novo exon splicing that enables the synthesis and secretion of mutant tetramers and homozygous nonsense mutations that lead to premature termination of translation and complete loss of function are associated with early-onset, severe phenotypes. In this review, we present the current state of diagnosis and research in the field of ColVI myopathies. The past decade has provided significant advances, with the identification of altered cellular functions in animal models of ColVI myopathies and in patient samples. In particular, mitochondrial dysfunction and a defect in the autophagic clearance system of skeletal muscle have recently been reported, thereby opening potential therapeutic avenues. Review ColVI is a heterotrimeric molecule composed of three Collagen VI: an important component of connective individual a(VI) chains that display a similar structure, tissues with a triple helical domain characterized by the repeti- Collagens are major constituents of the extracellular tion of the Gly-X-Y amino acid sequence, flanked by matrix (ECM), and are found in most connective tissues. globular domains homologous to von Willebrand factor They provide structural and mechanical stability to tis- A domains [16,17]. In addition to the well-known a1 sues, but they also play crucial roles in cell-ECM inter- (VI), a2(VI) and a3(VI) chains encoded in human by actions through various receptors [1]. In particular, the COL6A1, COL6A2 (located head-to-tail on chromo- collagen type VI (ColVI), an important component of some 21q22.3), and COL6A3 (on chromosome 2q37) skeletal muscle ECM, is involved in maintaining tissue genes [18], three novel chains, a4(VI), a5(VI) and a6 integrity by providing a structural link between different (VI), have recently been identified [19,20]. These chains constituents of connective-tissue basement membranes have high structural homology to the a3(VI) chain. In humans, the COL6A4, COL6A5 and COL6A6 genes are (for example, collagen types I and IV, biglycan, and dec- orin) and cells [2-15] (Figure 1). In addition to its struc- all located on chromosome 3q22.1, with the COL6A4 tural role, ColVI supports adhesion, spreading and gene being split by a chromosome break and thus not migration of cells, and cell survival, as discussed later in coding for a protein [19-21]. The murine orthologs of this review. these genes are organized in tandem on chromosome 9 (Col6a4, Col6a5 and Col6a6) and encode the a4(VI), a5 (VI) and a6(VI) chains. The expression pattern of the * Correspondence: v.allamand@institut-myologie.org three novel chains differs between mice and humans, Inserm, U974, Paris, France and also between fetal and adult tissues [19,20]. Full list of author information is available at the end of the article © 2011 Allamand et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Allamand et al. Skeletal Muscle 2011, 1:30 Page 2 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 1 Schematic representation of the collagen type VI (ColVI) intracellular assembly process, and interactions with skeletal muscle extracellular matrix (ECM) components. Individual a(VI) chains fold through their triple helical domains to form monomers (1:1:1 ratio) in the endoplasmic reticulum (ER), which further align in an anti-parallel manner as dimers and tetramers that are stabilized by disulfide bonds between cysteine residues (S = S links). Post-translational modifications (indicated in orange) take place in the ER and Golgi, followed by secretion of tetramers that align non-covalently end to end, to form beaded microfibrils in the ECM. ColVI interacts with collagenous and non- collagenous components of the basal lamina and interstitial matrix surrounding muscle fibers. Allamand et al. Skeletal Muscle 2011, 1:30 Page 3 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Importantly, in the context of ColVI myopathies, the a6 described separately but now recognized as the extreme (VI) chain is the only one expressed at high levels in ends of a continuous clinical spectrum [38,39] (Figure human skeletal muscle, at higher levels in fetal than 2). The severe endpoint of this spectrum corresponds to adult tissue [19]. In skin, a detailed analysis of the Ullrich congenital muscular dystrophy (UCMD, OMIM expression of the human a5(VI) and a6(VI) chains 254090; http://www.ncbi.nlm.nih.gov/omim), described revealed that both chains are expressed, albeit differ- in 1930 as ‘congenital atonic-sclerotic muscular dystro- ently, and that they are variably altered in tissues from phy’, emphasizing its early onset and the presence of patients with mutations in the COL6A1, COL6A2 and proximal joint contractures associated with a striking COL6A3 genes [22]. Interestingly, the COL6A5 gene had distal hyperlaxity [40,41]. Orthopedic deformities (joint previously been reported as associated with atopic der- contractures, scoliosis) and respiratory impairment with matitis under the name COL29A1 [23], but this associa- diaphragmatic failure generally develop within the first tion has recently been questioned [24,25]. The knee decade of life, and may be life-threatening. Arrest of osteoarthritis susceptibility locus DVWA was shown to motor milestones with no acquisition of walking ability correspond to the 5’ part of the split COL6A4 gene [21]. is seen in a subset of patients, but most children are Although largely ubiquitous, the expression of ColVI able to walk, and show later progression of muscle seems to be finely regulated in different cell types and weakness with loss of ambulation around 10 years of tissues, as shown for the murine Col6a1 gene. The iden- age, and a requirement for mechanical ventilation in late tification of a transcriptional enhancer located in the 5’- childhood or young adulthood [42,43]. flanking sequence of the gene points to a collaborative At the other end of the spectrum is the milder form crosstalk between myogenic and mesenchymal/endomy- Bethlem myopathy (BM, OMIM 158810), described in sial cells, enabling transcription of ColV in muscle con- 1976, which begins in the first or second decade, nective tissue [26-28]. although a neonatal history may be recognized, charac- The a1(VI), a2(VI) and a3(VI) chains assemble intra- terized by early contractures of finger flexors, wrist, cellularly as monomers (1:1:1 ratio), from their C-term- elbows and ankles [44,45]. Respiratory failure and distal inal ends, and subsequently form dimers (two anti- hyperlaxity are usually absent or are milder than in parallel, overlapping monomers) and tetramers (four UCMD, although the latter may not be so uncommon monomers) that are stabilized by disulfide bonds in very young children withBM. Thecourseisusually between cysteine residues of the three chains [29-34]. slow, with most of the patients remaining ambulatory. ColVI chains are subjected to extensive post-transla- However, progression of muscle weakness occurs often tional modifications such as hydroxylation of lysine and in the fifth decade, resulting in about 50% of patients proline residues [35], and glycosylation of hydroxyly- requiring walking aids or a wheelchair [46]. Intermediate sines, which have been shown to be essential for the tet- phenotypes have been described, and named ‘mild ramerization and further secretion of ColVI [36,37]. UCMD’ or ‘severe BM’, thereby reinforcing the notion Upon secretion, tetramers are further aligned end to of clinical overlap between Ullrich and Bethlem pheno- end as microfibrils in the extracellular space, with a types [38,39]. characteristic beaded appearance [33] (Figure 1). To Skin features such as follicular hyperkeratosis and date, somewhat contradictory results have been obtained hypertrophic scars or keloid formation are common regarding the possible assembly of the newly character- [38,39,42,43,47-49]. Other common findings include ized a(VI) polypeptides with the a1(VI), a2(VI) chains. normal cognitive abilities, normal or only slightly raised In transfection experiments, only a4(VI) appeared to serum creatine kinase (CK) levels, and absence of car- have this ability [19], whereas in mouse muscle, all three diac phenotype. Two other conditions that fall within were reported to do so [20]. Whether and how these the spectrum of ColVI myopathies have been documen- additional chains may fit in the pathogenesis of ColVI ted: autosomal dominant limb-girdle muscular dystro- myopathies remains unresolved to date, and needs to be phy (LGMD) (in three families) and, more recently, addressed more comprehensively. To date, in our cohort autosomal recessive myosclerosis myopathy (OMIM of patients, no pathogenic mutations have been found 255600) (in one family) [50,51]. by sequencing of the COL6A5 and COL6A6 genes in The prevalences of UCMD and BM in northern Eng- patients without mutations in the COL6A1-3 genes (V. land has recently been reported as 0.13 and 0.77 per Allamand, data not shown). 100,000, respectively, amounting collectively to 0.9 per 100,000 [52]. UCMD seems to be the second most com- Clinical phenotypes of collagen VI myopathies mon type of congenital muscular dystrophy (CMD) in The etiological definition of ColVI myopathies as a spe- Europe (behind laminin a2 chain deficiency; OMIM 607855) and also in Japan (behind Fukuyama congenital cific condition has evolved over the years with the blur- muscular dystrophy; OMIM 253800, [53]) and Australia ring of boundaries between two disorders, initially Allamand et al. Skeletal Muscle 2011, 1:30 Page 4 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 2 Clinical spectrum, associated spine deformation and muscle MRI in collagen type VI (ColVI) myopathies. (A),Early severe phenotypes, corresponding to classic Ullrich congenital muscular dystrophy (UCMD), (B) intermediate forms seen in children or adults and (C) less severe, classic Bethlem myopathy (BM) forms constitute the overlapping clinical presentations of ColVI myopathies. (D) Radiography showing the evolution of spine deformation in a patient presenting with a classic early-onset UCMD phenotype. T1 transverse section of Bethlem myopathy upper limb girdle (E) and (F) thighs. Note the fatty infiltration, which appears as hyperintense area on T1-weighted images, located around the triceps brachialis muscles in (E) and along the fascia of vastus lateralis and vastus medialis muscles in (F) (yellow arrows). (G) The concentric fatty involvement of the thigh muscles is also seen on whole body MRI. (Images courtesy of Drs Susana Quijano-Roy and Tanya Stojkovic). (behind a-dystroglycan glycosylation defects; [54]). In [55-57]. Imaging techniques, such as computed the cohort from northern England, BM emerges as the tomography or magnetic resonance imaging (MRI) of fourth most common myopathy behind myotonic dys- muscle, are now recognized as very helpful in the diag- trophy (OMIM 160900), facio-scapulo-humeral muscu- nostic approach of muscle disease, because there are lar dystrophy (OMIM 158900) and Duchenne/Becker specific patterns of muscle involvement in each of muscular dystrophy (OMIM 310200 and 300376) [52]. these contractile myopathies as reported for EDMD with LMNA mutations [58], muscular dystrophies with Differential diagnosis of ColVI-related myopathies rigidity of the spine [59], and ColVI myopathies With the most prominent clinical presentation of [58,60,61]. From these studies, the typical pattern of ColVI myopathies being muscle weakness and contrac- muscle involvement in ColVI myopathies is now con- tures, associated with variable degrees of hyperlaxity, sidered to be constituted by a diffuse, concentric hypo- an important difficulty lies in defining boundaries and density of the thigh muscles with relative sparing of contiguities, with the possible differential diagnosis the sartorius, gracilis and adductor longus muscles. including congenital myopathies, Emery-Dreifuss mus- The vasti muscles are the most affected muscles. In cular dystrophy (EDMD; OMIM 181350), LGMD, rigid addition, a peculiar centralareaofabnormalsignalis spine muscular dystrophies, and other diseases of con- seen within the rectus femoris, initially referred to as a nective tissues such as Ehlers-Danlos syndrome ‘central shadow’ [62]. Allamand et al. Skeletal Muscle 2011, 1:30 Page 5 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 In the context of the differential diagnosis, the absence in the COL6A1 and COL6A2 genes. The most common of raised CK levels, the lack of a cardiac phenotype, and types of mutations are point mutations, and mutations the presence of a specific MRI pattern are strongly sug- leading to premature termination codons (PTCs) and gestive of a ColVI myopathy. exon skipping (Figure 4). Among the former, missense changes affecting glycine residues in the triple helical Molecular diagnosis and genetics domains of the corresponding proteins are the most common, and are often dominant de novo. Because In light of the clinical variability and the overlapping these changes affect crucial amino acids within the col- presentation with other muscular disorders, a definite lagenous domains, they hamper triple-helix formation diagnosis can only be made after the identification of pathogenic mutations in one of the COL6A genes, [74-77]. Splice mutations resulting in in-frame exon which to date are restricted to COL6A1, COL6A2 and skipping are generally dominant de novo mutations, and COL6A3. However, the large size (106 coding exons in exons 16 of COL6A3 and 14 of COL6A1 seem to be total corresponding to 150 kb of genomic DNA) of preferentially affected, leading to UCMD or BM pheno- these genes makes routine molecular diagnostics costly types, respectively [53,75,78-83]. Nonsense mutations and time-consuming. The road to this ‘holy grail’ of and small deletions or insertions inducing PTCs within diagnosis is thus often lengthy and full of pitfalls, and the coding frame are mostly inherited as recessive muta- relies on a combination of clinical, biochemical and tions, and lead to loss of function of the protein molecular findings. [42,53,68,75,76,79-92]. These mutations are responsible Historically, muscle biopsies were the routine and pri- for most UCMD phenotypes. Nevertheless, it should be mary step undertaken for diagnostic purposes, and dou- noted that genotype-phenotype correlations are very dif- ble immunostaining with a basement-membrane marker ficult to identify. enabled recognition of ColVI deficiency in patients with It has recently been shown that all types of mutations UCMD [63], but not in patients with BM. The current alter transcript levels, and that in the case of PTC-bear- diagnostic method of determining ColVI involvement is ing transcripts, which are specifically degraded via the primarily based on immunocytochemistry of cultured nonsense-mediated mRNA decay (NMD [93,94]) path- skin fibroblasts, but this analysis is only available in a way, quantification of the three COL6A mRNAs is a limited number of laboratories to date. A number of helpful tool to pinpoint the mutated gene, thereby facili- antibodies recognizing human ColVI are now commer- tating these cumbersome molecular analyses [42]. The NMD-induced degradation of PTC-bearing transcripts cially available and may be used for such techniques; in may also, at least in part, explain why the parents of particular, the refined protocol proposed by Hicks et al. [64], using a polyclonal antibody raised against mature patients with UCMD who themselves harbor recessive ColVI from human placenta, has better sensitivity, espe- mutations are asymptomatic; their heterozygous status cially in fibroblast cultures from patients with BM sustains the expression of 50% of the ‘normal’ protein, (Figure 3). The absence or alteration of ColVI secretion thereby leading to a ‘functional loss of heterozygosity’. in cultured fibroblasts, associated with clinical symptoms The study by Briñas and collaborators also provided compatible with a diagnosis of ColVI myopathy, cer- some genotype-phenotype correlations in a cohort of tainly warrants further genetic analysis. patients with early-onset ColVI myopathy, showing that Over the past decade, the development of genetic stu- recessive mutations leading to PTC were associated with dies has demonstrated the heterogeneity and complexity severe phenotypes [42]. Genetic studies are further com- of the molecular mechanisms at play in ColVI myopa- plicated by a possibly variable penetrance as reported by thies. An autosomal recessive pattern of inheritance was Peat et al. [89]. initially thought to be involved in UCMD, and linkage Finally, the highly polymorphic nature of the COL6A analysis led to the identification of mutations in the genes makes it difficult to definitely assign pathogenicity COL6A2 and COL6A3 genes [65-67]. However, numer- to some variants, especially missense ones that do not ous dominant de novo mutations have now been shown affect glycine residues within the triple-helix domains of to be involved, accounting for more than 50% of the the proteins. In addition, these ‘polymorphisms’ may mutations causing UCMD [38,39,42,68]. Similarly, auto- very well play a role in the extreme clinical variability of somal dominant mutations were first identified in the these conditions, particularly in patients carrying identi- COL6A1 and COL6A2 genes in families with BM, sug- cal mutations but presenting with variable severity. gesting that BM was mostly familial and inherited as an The types of mutations identified also reflect the autosomal dominant disease [69], although rare de novo methods used in laboratories performing these analyses mutations and autosomal recessive mutations have now (for example, sequencing of genomic DNA or of the been reported [70-73]. To date, over 200 mutations coding sequences on cDNA), but the emergence of have been identified in these genes, mostly distributed high-throughput methods (arrays) is likely to allow the Allamand et al. Skeletal Muscle 2011, 1:30 Page 6 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 3 Collagen type VI (ColVI) expression study in cultured skin fibroblasts. (A) Representative images obtained using the protocol from [67] in which ColVI (red) is labeled with monoclonal antibody MAB1944 (Chemicon (now Millipore), Billerica, MA, USA) and perlecan (green) with monoclonal antibody MAB1948 (Chemicon). Note that ColVI expression appeared clearly altered in a patient with an early severe (ES) form and less so in patients with intermediate (Int) or Bethlem myopathy (BM) forms, compared with control fibroblasts (Cont). (B) Using the protocol of Hicks et al. [64], which detects ColVI (red) with polyclonal antibody Ab6588 (Abcam, Cambridge, UK) and fibronectin (green) with monoclonal antibody F15 (Sigma Chemical Co., St Louis, MO, USA), the sensitivity of the method is increased, and defective ColVI secretion could be detected in all patients’ samples. Insets indicate nuclei, labeled using DAPI. Bars are 50 μm. (Images courtesy of Corine Gartioux and Valérie Allamand). identification of as yet unknown or under-recognized proven central to understanding the cellular pathways pathogenic mechanisms, such as large gene rearrange- involved in these diseases. Homozygous animals were ments, or promoter or deep intronic mutations, as reported to develop a mild myopathic phenotype, and recently illustrated in two reports [95,96]. were initially described as a model of BM [97]. Interest- ingly, the diaphragm was the most affected muscle, with Animal models and pathophysiology signs of necrosis evidenced by uptake of Evan’s blue dye Limited access to muscle biopsies hinders extensive [97]. Subsequently, a latent mitochondrial dysfunction investigations of the specific cellular mechanisms leading accompanied by ultrastructural alterations of mitochon- to the development of the muscle pathology, and in dria and the sarcoplasmic reticulum, resulting in sponta- neous apoptosis, was found in about one-third of muscle vitro/ex vivo cellular systems only partially reproduce the complexity of the tissue. The development of the fibers [98]. Reduced contractile strength of the dia- first animal model of ColVI deficiency in 1998, engi- phragm and other muscle groups was also reported in -/- neered by invalidating the Col6a1 gene in mice, has Col6a1 mice in this initial study [98]. The maximal Allamand et al. Skeletal Muscle 2011, 1:30 Page 7 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 4 Repartition of the various types of mutations identified in the COL6A1, COL6A2 and COL6A3 genes. This schematic reflects, to the best of our ability, the distribution of 258 allelic mutations (98 on COL6A1, 113 on COL6A2 and 47 on COL6A3). Dominant de novo mutations represent 67% of the missense mutations, affecting glycine residues in the TH domains (Gly in TH), 57% of small deletions (< 5 amino acids) and 44% of splice-site mutations leading to in-frame exon skipping, whereas 97% of mutations leading to premature termination codons (PTCs) are familial (recessive or dominant). isometric tension generated by ColVI-deficient skinned showed that patients-derived skin fibroblasts behave dif- fibers from gastrocnemius was found to be reduced in a ferently from myoblasts in that respect, and also ques- recent report; however, using a protocol of eccentric tioned the specificity of this mitochondrial dysfunction contractions in vivo, no muscle force drop was found, [102], warranting further studies on the matter. indicating that the lack of ColVI does not impair myofi- A role for cell survival had previously been proposed brillar function [99]. Importantly, mitochondrial dys- for ColVI because it was shown to prevent anti-a1 function was also reported in cultured muscle cells from integrin-mediated apoptosis and trigger the downregula- patients and could be reversed by cyclosporin (Cs)A, an tion of bax, a pro-apoptotic molecule [103,104]. immunosuppressive drug that prevents the opening of Recently, a study of the autophagic process in muscles the mitochondrial permeability transition pore through of Col6a1 knockout mice revealed that autophagy was binding to cyclophilin D, and also inhibits the phospha- not induced efficiently [105]. The ensuing defective tase calcineurin [100,101]. Another in vitro study autophagy provides the link between the previously Allamand et al. Skeletal Muscle 2011, 1:30 Page 8 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 Figure 5 Current pathological hypotheses and therapeutic targets. The currently known cascade of main events leading to myofiber degeneration in ColVI-deficient skeletal muscle is shown. Mitochondrial dysfunction (due in part to the defective permeability transition pore (PTP) opening) triggers an energetic imbalance with the increased levels of phosphorylated adenosine monophosphate-activated protein kinase 2+ (p-AMPK), Ca overload and the production of reactive oxygen species (ROS). Lack of autophagy induction exacerbates the cellular dysfunction because defective mitochondria and proteins (such as p62 aggregates) are not cleared from the cytoplasm. Together, these defects lead to increased apoptosis. Potential therapeutic interventions are indicated in green. Allamand et al. Skeletal Muscle 2011, 1:30 Page 9 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 described mitochondrial dysfunction and myofiber a chemical derivative of (-)-deprenyl, which was shown degeneration, as abnormal organelles and molecules to reduce GAPDH-Siah1-mediated apoptosis in a mouse cannot be efficiently cleared from the cell. This study model of laminin a2 chain deficiency [114]. further showed that the forced induction of autophagy, Itshouldbe notedthattranslatingsome of this either by dietary restriction or by treatment with rapa- research from animal models to patients represents a mycin or CsA, ameliorated the phenotype of the challenging task, particularly because, to date, these -/- Col6a1 mice (Figure 5). A similar alteration of autop- drugs have not been approved for use in children, the hagy was also detected in muscle biopsies derived from patient population with the most severe forms of ColVI nine patients with UCMD or BM [105]. These data thus myopathies. In addition, there is concern about these provide a basis for novel therapeutic targets to promote therapeutic approaches because of the pleiotropic, and the elimination of defective organelles in ColVI-deficient potentially harmful, consequences of anti-apoptotic and/ skeletal muscle. or pro-autophagy treatments. Furthermore, such Morpholino-mediated knock-down of the col6a1 and approaches aiming at modulating downstream pathways col6a3 genes in zebrafish embryos showed that collagen would not address the primary defect in these disorders, VI deficiency significantly impairs muscle development that is, lack of ColVI in the connective tissue, and and function [106]. Increased apoptosis, partially pre- would thus need to be continually administered. For the vented by CsA treatment, was also described in the zeb- sake of discussion, several alternative, and not necessa- rafish morphants [106]. As in other instances, rily exclusive, therapeutic avenues that would sustain re- perturbation of muscle components leads to a more expression of ColVI may be envisioned. These severe phenotype in zebrafish than in mouse models, approaches may consist of gene-based therapies, such as which may in part be due to intrinsic differences in vector delivery of ColVI-coding sequence, and antisense muscle development in these species, especially in terms inhibition of mutant transcripts exerting dominant- of timing. Zebrafish models have emerged as major in negative effects [96]. Additionally, as nonsense muta- vivo models of neuromuscular disorders, and seem to be tions leading to PTCs are often associated with early- particularly well suited for whole-organism screens for onset, severe phenotypes [42], pharmacological potential pharmacological treatments, as recently illu- approaches aiming to ‘force’ translation of PTCs (a phe- strated in zebrafish models of Duchenne muscular dys- nomenon known as ‘translational readthrough’ [115]) trophy [107]. may prove beneficial for a subset of patients carrying these types of mutations. However, the complex assem- Therapeutic intervention bly process and regulation of ColVI may prove challen- ging and may limit the realistic options to be To date, no curative treatment exists for these disorders, and most patients rely on supportive treatment of symp- investigated. toms, usually involving orthopedic (spinal deformations, contractures) and respiratory complications [108]. Conclusions The unveiling of mitochondrial dysfunction led to an The past decade of research on neuromuscular disorders open pilot trial in five patients with UCMD or BM trea- has proven very exciting, and has seen ColVI myopa- ted orally with CsA for 1 month [109]. This study thies emerge as an important set of disorders, rather reported normalization of the mitochondrial dysfunction under-recognized until recently. Many challenges remain and decrease of apoptosis of muscle cells following this despite the tremendous advances in the understanding short-term treatment [110,111]. Longer treatment (up to of their genetic, biochemical and pathophysiological 2 years) had some beneficial effect on muscle function bases. It is hoped that the decade(s) to come will see the in these patients but did not prevent progression of the development of safe and efficient therapies for these dis- disease in the children [38]. Debio-025 (D-MeAla3Et- orders. Consequently, as for other rare diseases, the Val4-cyclosporin; DebioPharm) prevents the inappropri- scientific community, and patient organizations, and ate opening of the mitochondrial permeability transition patients and their families have become increasingly pore (PTP) without interfering with calcineurin [112], aware of the need for databases, both clinical and and was shown to restore mitochondrial function in cul- genetic, to facilitate recruitment of patients for upcom- -/- tured muscle cells of patients [100] and in Col6a1 ing clinical trials. mice [113]. Debio-025 is currently being tested in a phase II clinical trial in patients with chronic hepatitis List of abbreviations used C. Another anti-apoptotic pharmacological agent that is BM: Bethlem myopathy; ColVI: collagen type VI; COL6A: gene(s) encoding the being investigated in the context of ColVI myopathies is alpha chain(s) of collagen VI; CsA: cyclosporin A; DAPI: 4’,6-diamidino-2- phenylindole; EDMD: Emery-Dreifuss muscular dystrophy; EDS: Ehlers-Danlos Omigapil (N-(dibenz(b, f)oxepin-10-ylmethyl)-N-methyl- syndrome; LMNA: gene encoding lamin A/C; MDC1A: congenital muscular N-prop-2-ynylamine maleate; Santhera Pharmaceuticals), Allamand et al. Skeletal Muscle 2011, 1:30 Page 10 of 13 http://www.skeletalmusclejournal.com/content/1/1/30 dystrophy with laminin α2 chain deficiency; PTP: permeability transition pore; Received: 24 March 2011 Accepted: 23 September 2011 MRI: magnetic resonance imaging; PTC: premature termination codon; ROS: Published: 23 September 2011 reactive oxygen species; SEPN1: gene encoding selenoprotein N; TNXB: gene encoding tenascin-X; UCMD: Ullrich congenital muscular dystrophy References 1. Leitinger B, Hohenester E: Mammalian collagen receptors. Matrix Biol 2007, Acknowledgements 26:146-155. We thank Corine Gartioux and Céline Ledeuil for excellent technical skills. 2. Bidanset D, Guidry C, Rosenberg L, Choi H, Timpl R, Hook M: Binding of This study was funded by the Institut National de la Santé et de la the proteoglycan decorin to collagen type VI. J Biol Chem 1992, Recherche Médicale (Inserm), Association Française contre les Myopathies 267:5250-5256. 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Skeletal MuscleSpringer Journals

Published: Sep 23, 2011

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