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Carsten G. Bönnemann - One of the best experts on this subject based on the ideXlab platform.
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pathogenic variants in col6a3 cause ullrich like congenital muscular dystrophy in young labrador retriever dogs
Neuromuscular Disorders, 2020Co-Authors: Veronique Bolduc, Katie M Minor, Rupleen Kaur, Steven G Friedenberg, Samantha Van Buren, Ling T Guo, Joseph C Glennon, Katia Marionihenry, James R Mickelson, Carsten G. BönnemannAbstract:The collagen VI-related muscular dystrophies in people include a broad spectrum of diseases ranging from the severe Ullrich congenital muscular dystrophy to the mild Bethlem Myopathy. Clinical features are attributable to both muscle and connective tissue and include progressive muscle weakness and respiratory failure, hyperlaxity of distal joints, and progressive contracture of large joints. Here we describe two different COL6A3 pathogenic variants in Labrador Retriever dogs that result in autosomal recessive or autosomal dominant congenital myopathies with hyperlaxity of distal joints and joint contracture, similar to the condition in people.
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Spontaneous keloid formation in patients with Bethlem Myopathy
Neurology, 2012Co-Authors: James J Collins, Volker Straub, A. Reghan Foley, Carsten G. BönnemannAbstract:A 32-year-old woman and a 50-year-old man with clinically typical Bethlem Myopathy developed seemingly spontaneous keloids on their shoulder region (figure). The patients did not recall any significant trauma to the skin of this region.
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The collagen VI-related myopathies: muscle meets its matrix
Nature Reviews Neurology, 2011Co-Authors: Carsten G. BönnemannAbstract:In this article, Carsten Bönnemann describes the clinical and diagnostic features of the entire spectrum of collagen VI-related myopathies, ranging from severe Ullrich congenital muscular dystrophy to mild Bethlem Myopathy. He also considers the genetic and molecular mechanisms that underlie this group of diseases, and discusses current and future approaches to treatment. The collagen VI-related Myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related Myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem Myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes— COL6A1, COL6A2 , and COL6A3 —can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.
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the collagen vi related myopathies muscle meets its matrix
Nature Reviews Neurology, 2011Co-Authors: Carsten G. BönnemannAbstract:In this article, Carsten Bonnemann describes the clinical and diagnostic features of the entire spectrum of collagen VI-related myopathies, ranging from severe Ullrich congenital muscular dystrophy to mild Bethlem Myopathy. He also considers the genetic and molecular mechanisms that underlie this group of diseases, and discusses current and future approaches to treatment.
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the collagen vi related myopathies ullrich congenital muscular dystrophy and Bethlem Myopathy
Handbook of Clinical Neurology, 2011Co-Authors: Carsten G. BönnemannAbstract:Abstract Mutations in the genes COL6A1, COL6A2, and COL6A3, coding for three α chains of collagen type VI, underlie a spectrum of myopathies, ranging from the severe congenital muscular dystrophy-type Ullrich (UCMD) to the milder Bethlem Myopathy (BM), with disease manifestations of intermediate severity in between. UCMD is characterized by early‐onset weakness, associated with pronounced distal joint hyperlaxity and the early onset or early progression of more proximal contractures. In the most severe cases ambulation is not achieved, or it may be achieved only for a limited period of time. BM may be of early or later onset, but is milder in its manifestations, typically allowing for ambulation well into adulthood, whereas typical joint contractures are frequently prominent. A genetic spectrum is emerging, with BM being caused mostly by dominantly acting mutations, although rarely recessive inheritance of BM is also possible, whereas both dominantly as well as recessively acting mutations underlie UCMD.
Shireen R. Lamandé - One of the best experts on this subject based on the ideXlab platform.
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Reply to Sabatelli et al.: Detecting collagen VI in Bethlem Myopathy.
The Journal of biological chemistry, 2015Co-Authors: Shireen R. LamandéAbstract:This is a response to a letter by Sabatelli et al. (1). In their letter, Sabatelli et al. (1) refer to our recent paper on a Bethlem Myopathy patient with a homozygous COL6A2 p.D871N mutation. The authors are concerned that our data are inconsistent because we reported that collagen VI staining was absent in muscle when using monoclonal antibody VI-26 but present in very reduced amounts in cultured fibroblast extracellular matrix when detected with monoclonal antibody 3C4 (2). We agree that based on our in vitro fibroblast data it is likely that this patient's muscle contains some collagen VI, and we believe that our staining conditions were not sufficiently sensitive to detect the small amount present even though collagen VI staining was strong in the control muscle. We had this in mind when we said “collagen VI was not detected in UCMD65 muscle” and used the phrase “absent collagen VI staining” under “Results.” Unfortunately we used the term “absent collagen VI” in the subheading, and this has resulted in the inadvertent apparent inconsistency. The collagen VI staining was actually done on sections of paraffin-embedded muscle, not frozen sections as suggested under “Experimental Procedures,” and this is why we used an antigen retrieval protocol, which resulted in strong staining in the control muscle (2). We apologize for omitting this important detail under “Experimental Procedures.”
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aberrant mitochondria in a Bethlem Myopathy patient with a homozygous amino acid substitution that destabilizes the collagen vi α2 vi chain
Journal of Biological Chemistry, 2015Co-Authors: Laura Zamurs, Shireen R. Lamandé, Miguel A Idoate, Eric Hanssen, Asier Gomezibanez, Pau PastorAbstract:Abstract Bethlem Myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem Myopathy is relatively mild and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem Myopathy is rare and our understanding of the molecular pathology is limited. We studied a patient with Bethlem Myopathy. Electron microscopy of his muscle biopsy revealed abnormal mitochondria. We identified a homozygous COL6A2 p.D871N amino acid substitution in the C-terminal C2 A-domain. Mutant α2(VI) chains are unable to associate with α1(VI) and α3(VI) and are degraded by the proteasomal pathway. Some collagen VI is assembled, albeit more slowly than normal, and is secreted. These molecules contain the minor α2(VI) C2a splice form which has an alternative C-terminus that does include the mutation. Collagen VI tetramers containing the α2(VI) C2a chain do not assemble efficiently into microfibrils and there is a severe collagen VI deficiency in the extracellular matrix. We expressed wild-type and mutant α2(VI) C2 domains in mammalian cells and showed that while wild-type C2 domains are efficiently secreted, the mutant p.D871N domain is retained in the cell. These studies shed new light on the protein domains important for intracellular and extracellular collagen VI assembly and emphasise the importance of molecular investigations for families with collagen VI disorders to ensure accurate diagnosis and genetic counselling.
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Variable penetrance of COL6A1 null mutations: implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families.
Neuromuscular disorders : NMD, 2007Co-Authors: Rachel A. Peat, Naomi L. Baker, Kathryn N. North, Kristi J. Jones, Shireen R. LamandéAbstract:Abstract Collagen VI mutations cause mild Bethlem Myopathy and severe, progressive Ullrich congenital muscular dystrophy (UCMD). We identified a novel homozygous COL6A1 premature termination mutation in a UCMD patient that causes nonsense-mediated mRNA decay. Collagen VI microfibrils cannot be detected in muscle or fibroblasts. The parents are heterozygous carriers of the mutation and their fibroblasts produce reduced amounts of collagen VI. The molecular findings in the parents are analogous to those reported for a heterozygous COL6A1 premature termination mutation that causes Bethlem Myopathy. However, the parents of our UCMD proband are clinically normal. The proband's brother, also a carrier, has clinical features consistent with a mild collagen VI phenotype. Following a request for prenatal diagnosis in a subsequent pregnancy we found the fetus was a heterozygous carrier indicating that it would not be affected with severe UCMD. COL6A1 premature termination mutations exhibit variable penetrance necessitating a cautious approach to genetic counselling.
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Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy
Human molecular genetics, 2004Co-Authors: Naomi L. Baker, Matthias Mörgelin, Rachel A. Peat, John F. Bateman, Nathalie Goemans, Kathryn N. North, Shireen R. LamandéAbstract:Mutations in the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause Bethlem Myopathy and Ullrich congenital muscular dystrophy (UCMD). UCMD, a severe disorder characterized by congenital muscle weakness, proximal joint contractures and marked distal joint hyperextensibility, has been considered a recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In contrast, the milder disorder Bethlem Myopathy shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2 and COL6A3. This model, where dominant mutations cause mild Bethlem Myopathy and recessive mutations cause severe UCMD was recently challenged when a patient with UCMD was shown to have a heterozygous in-frame deletion in COL6A1. We have studied five patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain, one in the alpha1(VI) chain, one in alpha2(VI) and one in alpha3(VI). Collagen VI protein biosynthesis and assembly studies showed that these mutations act in a dominant negative fashion and result in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of alpha2(VI), which prevented collagen VI assembly. No collagen VI mutations were found in the fifth patient. These data demonstrate that rather than being a rare cause of UCMD, dominant mutations are common in UCMD, now accounting for four of the 14 published cases. Mutation detection in this disorder remains critical for accurate genetic counseling of patients and their families.
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Kinked Collagen VI Tetramers and Reduced Microfibril Formation as a Result of Bethlem Myopathy and Introduced Triple Helical Glycine Mutations
The Journal of biological chemistry, 2001Co-Authors: Shireen R. Lamandé, Matthias Mörgelin, G J Jobsis, Frank Baas, Carly Selan, John F. BatemanAbstract:Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, and COL6A3, are the cause of the dominantly inherited disorder, Bethlem Myopathy. Glycine mutations that interrupt the Gly-X-Y repetitive amino acid sequence that forms the characteristic collagen triple helix have been defined in four families; however, the effects of these mutations on collagen VI biosynthesis, assembly, and structure have not been determined. In this study, we examined the consequences of Bethlem. Myopathy triple helical glycine mutations in the alpha1(VI) and alpha2(VI) chains, as well as engineered alpha3(VI) triple helical glycine mutations. Although the Bethlem Myopathy and introduced mutations that are toward the N terminus of the triple helix did not measurably affect collagen VI intracellular monomer, dimer, or tetramer assembly, or secretion, the introduced mutation toward the C terminus of the helix severely impaired association of the mutant alpha3(VI) chain with alpha1(VI) and alpha2(VI). Association of the three chains was not completely prevented, however; and some non-disulfide bonded tetramers were secreted. Examination of the secreted Bethlem Myopathy and engineered mutant collagen VI by negative staining electron microscopy revealed the striking finding that in all the cell lines a significant proportion of the tetramers contained a kink in the supercoiled triple helical region. Collagen VI tetramers from all of the mutant cell lines also showed a reduced ability to form microfibrils. These results provide the first evidence of the biosynthetic consequences of collagen VI triple helical glycine mutations and indicate that Bethlem Myopathy results not only from the synthesis of reduced amounts of structurally normal protein but also from the presence of mutant collagen VI in the extracellular matrix.
Luciano Merlini - One of the best experts on this subject based on the ideXlab platform.
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Pathophysiological Mechanisms of Sarcopenia in Aging and in Muscular Dystrophy: A Translational Approach - Editorial: Pathophysiological Mechanisms of Sarcopenia in Aging and in Muscular Dystrophy: A Translational Approach
Frontiers in aging neuroscience, 2015Co-Authors: Luciano Merlini, Paolo Bonaldo, Emanuele MarzettiAbstract:Editorial: Pathophysiological mechanisms of sarcopenia in aging and in muscular dystrophy: a translational approach::Shorter telomeres in peripheral blood mononuclear cells from older persons with sarcopenia: results from an exploratory study::Regulation of satellite cell function in sarcopenia::Mitochondrial involvement and impact in aging skeletal muscle::The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy::Qualitative alteration of peripheral motor system begins prior to appearance of typical sarcopenia syndrome in middle-aged rats::New pathobiochemical insights into dystrophinopathy from the proteomics of senescent mdx mouse muscle::Myogenic potential of canine craniofacial satellite cells::Degeneration of neuromuscular junction in age and dystrophy::RNA transcription and maturation in skeletal muscle cells are similarly impaired in myotonic dystrophy and sarcopenia: the ultrastructural evidence::Quantitative ultrasound: measurement considerations for the assessment of muscular dystrophy and sarcopenia::Borderlines between sarcopenia and mild late-onset muscle disease::Sarcopenia and physical frailty: two sides of the same coin::Pre-hospital dietary intake correlates with muscle mass at the time of fracture in older hip-fractured patients::Pompe disease: from pathophysiology to therapy and back again::Skeletal muscle homeostasis in Duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy::Laminin a2 chain-deficiency is associated with microRNA deregulation in skeletal muscle and plasma::Pathogenic mechanisms in centronuclear myopathies::Insights into muscle degeneration from heritable inclusion body myopathies::Cyclosporin A promotes in vivo myogenic response in collagen VI-deficient myopathic mice::Sarcopenia and sarcopenic obesity in patients with muscular dystrophy::Oculopharyngeal muscular dystrophy as a paradigm for muscle aging::Aggresome–autophagy involvement in a sarcopenic patient with rigid spine syndrome and a p.C150R mutation in FHL1 gene::Electrical stimulation counteracts muscle decline in seniors::Fetal stem cells and skeletal muscle regeneration: a therapeutic approach::New molecular targets and lifestyle interventions to delay aging sarcopenia::Nutritional status evaluation in patients affected by Bethlem Myopathy and Ullrich congenital muscular dystrophy::Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem Myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors
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detecting collagen vi in Bethlem Myopathy
Journal of Biological Chemistry, 2015Co-Authors: Patrizia Sabatelli, Francesca Gualandi, Paolo Bonaldo, Luciano MerliniAbstract:Zamurs et al. (1) investigated the functional consequences of a homozygous COL6A2 p.D871N mutation in muscle biopsy and fibroblast cultures of a recessive Bethlem Myopathy patient. The authors reported the absence of collagen VI (col6) in muscle biopsy, a pattern considered distinctive for Ullrich congenital muscular dystrophy (UCMD). This finding appears inconsistent with the data provided for the patient's skin fibroblasts, which clearly show that col6 was secreted in the extracellular matrix (1). Moreover, other authors showed that recessive mutations in the α2(VI) C2 domain, with consequences similar to those reported for this patient, cause a partial col6 deficiency in muscle biopsies (2, 3).
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Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.
Frontiers in aging neuroscience, 2014Co-Authors: Alessandra Zulian, Nadir M. Maraldi, Francesca Tagliavini, Erika Rizzo, Camilla Pellegrini, Francesca Sardone, Nicoletta Zini, Spartaco Santi, Cesare Faldini, Luciano MerliniAbstract:Ullrich congenital muscular dystrophy and Bethlem Myopathy are caused by mutations in collagen VI genes, which encode an extracellular matrix protein; yet mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high conductance channel which causes a shortage in ATP production. We find that melanocytes do not produce collagen VI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myooathy patients display increased size, reduced matrix density and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem Myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem Myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013 Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy. J Cell Physiol 228, 1323-1331), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in collagen VI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.
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Nutritional status evaluation in patients affected by Bethlem Myopathy and ullrich congenital muscular dystrophy.
Frontiers in aging neuroscience, 2014Co-Authors: Silvia Toni, Luciano Merlini, Riccardo Morandi, Marcello Busacchi, Lucia Tardini, Nino Carlo Battistini, Massimo PellegriniAbstract:Collagen VI mutations lead to disabling myopathies like Bethlem Myopathy (BM) and Ullrich Congenital Muscular Dystrophy (UCMD). We have investigated the nutritional and metabolic status of one UCMD and seven BM patients (5 female, 3 male, mean age 31 ± 9 years) in order to find a potential metabolic target for nutritional intervention. For this study, we used standard anthropometric tools, such as BMI evaluation and body circumference measurements. All results were compared to Dual Energy X ray Absorptiometry (DXA), considered the “gold standard” method. Energy intake of each patient was evaluated through longitudinal methods (7-day food diary) while Resting Energy Expenditure (REE) was predicted using specific equations and measured by indirect calorimetry. Clinical evaluation included general and nutritional blood and urine laboratory analyses and quantitative muscle strength measurement by hand-held dynamometry. BM and UCMD patients showed an altered body composition, characterized by low Free Fat Mass (FFM) and high Fat Mass (FM), allowing us to classify them as sarcopenic, and all but one as sarcopenic-obese. Another main result was the negative correlation between REE/FFM ratio (basal energy expenditure per kg of fat-free mass) and the severity of the disease, as defined by the muscle megascore (Correlation Coefficient -0.955, P value < 0.001). We postulate that the increase of the REE/FFM ratio in relation to the severity of the disease may be due to an altered and pathophysiological loss of energetic efficiency at the expense of skeletal muscle. We show that a specific metabolic disequilibrium is related to the severity of the disease, which may represent a target for a nutritional intervention in these patients.
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Body Composition, Muscle Strength, and Physical Function of Patients with Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy
TheScientificWorldJournal, 2013Co-Authors: Maria Teresa Miscione, Cesare Faldini, Francesca Bruno, Claudio Ripamonti, Giuliana Nervuti, Riccardo Orsini, Massimo Pellegrini, Daniela Cocchi, Luciano MerliniAbstract:Objective. To determine the contributions of body mass, adiposity, and muscularity to physical function and muscle strength in adult patients with Bethlem Myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). Materials and Methods. Evaluation involved one UCMD and 7 BM patients. Body composition was determined by body mass index (BMI) and dual-energy-X-ray-absorptiometry (DXA), muscle strength by dynamometry, physical function by the distance walked in 6 minutes (6MWD), forced vital capacity (FVC) by a spirometer. Results. Six participants were of normal weight and 2 overweight based on BMI; all were sarcopenic based on appendicular fat free mass index (AFFMI); and 7 were sarcopenic obese based on AFFMI and % fat mass. Average muscle strength was reduced below 50% of normal. The 6MWD was in BM patients 30% less than normal. FVC was reduced in 4 of the BM patients. Muscle strength had a good correlation with the physical function variables. Correlation between muscle strength and BMI was poor; it was very high with AFFMI. AFFMI was the best single explicator of muscle strength and physical function. Conclusion. Muscle mass determined by DXA explains most of the variability of the measures of muscle strength and physical function in patients with BM and UCMD.
Mon-li Chu - One of the best experts on this subject based on the ideXlab platform.
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COL6A1 genomic deletions in Bethlem Myopathy and Ullrich muscular dystrophy
Annals of neurology, 2005Co-Authors: Guglielmina Pepe, Rui Zhu Zhang, Betti Giusti, Laura Lucarini, Te-cheng Pan, Susana Quijano-roy, C. Gartioux, Katharine Bushby, Pascale Guicheney, Mon-li ChuAbstract:We have identified highly similar heterozygous COL6A1 genomic deletions, spanning from intron 8 to exon 13 or intron 13, in two patients with Ullrich congenital muscular dystrophy and the milder Bethlem Myopathy. The 5' breakpoints of both deletions are located within a minisatellite in intron 8. The mutations cause in-frame deletions of 66 and 84 amino acids in the amino terminus of the triple-helical domain, leading to intracellular accumulation of mutant polypeptides and reduced extracellular collagen VI microfibrils. Our studies identify a deletion-prone region in COL6A1 and suggest that similar mutations can lead to congenital muscle disorders of different clinical severity.
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new molecular mechanism for ullrich congenital muscular dystrophy a heterozygous in frame deletion in the col6a1 gene causes a severe phenotype
American Journal of Human Genetics, 2003Co-Authors: Te-cheng Pan, Carsten G. Bönnemann, Suely Kazue Nagahashi Marie, Rui Zhu Zhang, Dominick Sudano, Mon-li ChuAbstract:Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem Myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33–amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem Myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations.
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Novel COL6A1 splicing mutation in a family affected by mild Bethlem Myopathy
Muscle & nerve, 2002Co-Authors: Olga Camacho Vanegas, Luciano Merlini, Patrizia Sabatelli, Marta Columbaro, Mon-li Chu, Rui Zhu Zhang, Giovanna Lattanzi, Paola Bencivenga, Betti Giusti, Guglielmina PepeAbstract:Bethlem Myopathy is an early-onset benign Myopathy characterized by proximal muscular weakness and multiple flexion contractures. It is a dominantly inherited disorder associated with mutations in the three COL6 genes encoding type VI collagen. We detected a ga substitution at +1 position of COL6A1 intron 3 in a four-generation Italian family affected by a mild form of Bethlem Myopathy. The mutation results in the activation of a cryptic splice donor site at the 3′ end of exon 3, leading to the loss of 66 nucleotides and an “in-frame” deletion of 22 amino acids in the NH2-domain. Molecular analysis on fibroblasts of the propositus showed that the mutated mRNA was present and stable, but the mutated protein could not be detected. Western blot and immunofluorescence analyses showed a decreased level of collagen VI synthesis and deposition in fibroblasts of the propositus. Together, the results suggest that the mutated protein was highly unstable and rapidly degraded, and that the mild phenotype was caused by a reduced amount of normal collagen VI microfibrils. In addition, we demonstrated that lymphocytes can be used for the first mutation screening analysis of patients with Bethlem Myopathy. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
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A Bethlem Myopathy Gly to Glu mutation in the von Willebrand factor A domain N2 of the collagen α3(VI) chain interferes with protein folding
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2000Co-Authors: Takako Sasaki, Marcy C Speer, Rup Tandan, Rui Zhu Zhang, Erhard Hohenester, Susan Gotta, Rupert Timpl, Mon-li ChuAbstract:A single G1679E mutation in the amino-terminal globular domain N2 of the α3 chain of type VI collagen was found in a large family affected with Bethlem Myopathy. Recombinant production of N2 (∼200 residues) in transfected mammalian cells has now been used to examine the possibility that the mutation interfered with protein folding. The wild-type form and a G1679A mutant were produced at high levels and shown to fold into a stable globular structure. Only a small amount of secretion was observed for mutants G1679E and G1679Q, which apparently were efficiently degraded within the cells. Homology modeling onto the related von Willebrand factor A1 structure indicated that substitution of G1679 by the bulky E or Q cannot be accommodated without considerable changes in the folding pattern. This suggests protein misfolding as a molecular basis for this particular mutation in Bethlem Myopathy, in agreement with radioimmunoassay data showing reduced levels of domain N2 in cultured fibroblasts from two patients.—Sa...
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a novel de novo mutation in the triple helix of the col6a3 gene in a two generation italian family affected by Bethlem Myopathy a diagnostic approach in the mutations screening of type vi collagen
Neuromuscular Disorders, 1999Co-Authors: Luciano Merlini, Mon-li Chu, Betti Giusti, Guglielmina Pepe, Enrico Bertini, T Brunelli, Paolo Comeglio, Biagio Saitta, Giorgio FedericiAbstract:Abstract Bethlem Myopathy is an autosomal dominant inherited disease producing a mild neuromuscular disorder, mainly characterized by muscular weakness and multiple joint contractures. Bethlem Myopathy is caused by mutations in one of the three chains of collagen type VI. Here we report the clinical description and the molecular characterization of the defect in a two-generation Italian family in which a Gly→Arg substitution disrupts the triple helix structure of the α 3 chain of collagen type VI, an ubiquitous glycoprotein of the extracellular matrix. In this family the identification of the mutation also allowed one to exclude the disease in the grandfather. It is noteworthy that the father of the proband carries a de novo mutation, the first described for Bethlem Myopathy.
Guglielmina Pepe - One of the best experts on this subject based on the ideXlab platform.
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COL6A1 genomic deletions in Bethlem Myopathy and Ullrich muscular dystrophy
Annals of neurology, 2005Co-Authors: Guglielmina Pepe, Rui Zhu Zhang, Betti Giusti, Laura Lucarini, Te-cheng Pan, Susana Quijano-roy, C. Gartioux, Katharine Bushby, Pascale Guicheney, Mon-li ChuAbstract:We have identified highly similar heterozygous COL6A1 genomic deletions, spanning from intron 8 to exon 13 or intron 13, in two patients with Ullrich congenital muscular dystrophy and the milder Bethlem Myopathy. The 5' breakpoints of both deletions are located within a minisatellite in intron 8. The mutations cause in-frame deletions of 66 and 84 amino acids in the amino terminus of the triple-helical domain, leading to intracellular accumulation of mutant polypeptides and reduced extracellular collagen VI microfibrils. Our studies identify a deletion-prone region in COL6A1 and suggest that similar mutations can lead to congenital muscle disorders of different clinical severity.
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Novel COL6A1 splicing mutation in a family affected by mild Bethlem Myopathy
Muscle & nerve, 2002Co-Authors: Olga Camacho Vanegas, Luciano Merlini, Patrizia Sabatelli, Marta Columbaro, Mon-li Chu, Rui Zhu Zhang, Giovanna Lattanzi, Paola Bencivenga, Betti Giusti, Guglielmina PepeAbstract:Bethlem Myopathy is an early-onset benign Myopathy characterized by proximal muscular weakness and multiple flexion contractures. It is a dominantly inherited disorder associated with mutations in the three COL6 genes encoding type VI collagen. We detected a ga substitution at +1 position of COL6A1 intron 3 in a four-generation Italian family affected by a mild form of Bethlem Myopathy. The mutation results in the activation of a cryptic splice donor site at the 3′ end of exon 3, leading to the loss of 66 nucleotides and an “in-frame” deletion of 22 amino acids in the NH2-domain. Molecular analysis on fibroblasts of the propositus showed that the mutated mRNA was present and stable, but the mutated protein could not be detected. Western blot and immunofluorescence analyses showed a decreased level of collagen VI synthesis and deposition in fibroblasts of the propositus. Together, the results suggest that the mutated protein was highly unstable and rapidly degraded, and that the mild phenotype was caused by a reduced amount of normal collagen VI microfibrils. In addition, we demonstrated that lymphocytes can be used for the first mutation screening analysis of patients with Bethlem Myopathy. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
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Muscle MRI findings in a three-generation family affected by Bethlem Myopathy
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2002Co-Authors: Eugenio Mercuri, Joanna M Allsop, Guglielmina Pepe, C. Cini, Serena J. Counsell, Zuella Zolkipli, Heinz Jungbluth, Caroline Sewry, Susan C. Brown, Francesco MuntoniAbstract:We report clinical and muscle magnetic resonance imaging (MRI) findings in three individuals (aged 6, 26 and 73 years) from a three-generation family with Bethlem Myopathy, confirmed by molecular genetic analysis which showed an exon skipping mutation in the COL6A1 gene. The clinical severity ranged from mild proximal weakness and distal laxity in the younger patients, to inability to stand or walk and severe contractures in the 76-year-old grandmother. The pattern of muscle involvement showed variable severity in parallel with the severity of motor function impairment. Although there was a marked variability in the severity of the MRI findings, it was possible to recognize a specific pattern of muscle involvement in all three patients. This consisted of involvement of the peripheral region of the vastus lateralis and hamstrings muscles with relative sparing of their central part. This was best appreciated in the third decade of life, but could also be identified both in the younger patient with minimal MRI changes and in the oldest patient, despite her more severe and diffuse muscle involvement. This report suggests that muscle MRI could be used as an additional tool to establish the pattern and the degree of muscle involvement in patients with Bethlem Myopathy. Further studies in a larger cohort are needed to evaluate the specificity of these findings.
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Collagen type VI and related disorders: Bethlem Myopathy and Ullrich scleroatonic muscular dystrophy
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2002Co-Authors: Enrico Bertini, Guglielmina PepeAbstract:Collagen type VI is a glycoprotein made up of three genetically distinct a chains, a1(VI), a2(VI) and a3(VI), which assemble in a short central triple helix structure that joins two large globular domains. The heterotrimeric monomers associate in dimers and then in tetramers, intracellularly. Tetramers are secreted out of the cell into the extracellular matrix to assemble in an end-to-end fashion to form microfibrils that are characterized by a band of periodicity of 100 nm1,2 (Fig. 1). Collagen type VI is ubiquitously distributed in the connective tissues1 and is particularly abundant around cells, associated with interstitial collagen fibres types I–III, with a possible role as substrate for the attachment of cells and in anchoring collagen fibres, nerves and blood vessels to the surrounding connective tissue.3 The three chains are encoded by COL6A1, COL6A2 and COL6A3 genes; the first two are localized on chromosome 21q22.3 while the latter is located on chromosome 2q37. COL6 genomic DNA sizes range between 23 and 100 kb, subdivided into 28–44 exons; the mRNAs are 3.5–10 kb long.4,5 Between 1996 and 1998 the three genes were found to be associated with Bethlem Myopathy.6,7 The association demonstrates the tissue-specific importance of collagen type VI for skeletal muscle. More recently, a second disease – Ullrich scleroatonic muscular dystrophy, has been demonstrated to be associated with the COL6A2 gene by the discovery of recessive mutations in three unrelated patients and their families.8
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a novel de novo mutation in the triple helix of the col6a3 gene in a two generation italian family affected by Bethlem Myopathy a diagnostic approach in the mutations screening of type vi collagen
Neuromuscular Disorders, 1999Co-Authors: Luciano Merlini, Mon-li Chu, Betti Giusti, Guglielmina Pepe, Enrico Bertini, T Brunelli, Paolo Comeglio, Biagio Saitta, Giorgio FedericiAbstract:Abstract Bethlem Myopathy is an autosomal dominant inherited disease producing a mild neuromuscular disorder, mainly characterized by muscular weakness and multiple joint contractures. Bethlem Myopathy is caused by mutations in one of the three chains of collagen type VI. Here we report the clinical description and the molecular characterization of the defect in a two-generation Italian family in which a Gly→Arg substitution disrupts the triple helix structure of the α 3 chain of collagen type VI, an ubiquitous glycoprotein of the extracellular matrix. In this family the identification of the mutation also allowed one to exclude the disease in the grandfather. It is noteworthy that the father of the proband carries a de novo mutation, the first described for Bethlem Myopathy.