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[PMID]:28927399
[Au] Autor:Bánfai Z; Hadzsiev K; Pál E; Komlósi K; Melegh M; Balikó L; Melegh B
[Ad] Endereço:Department of Medical Genetics, University of Pécs, Szigeti út 12, Pécs, H-7624, Hungary.
[Ti] Título:Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.
[So] Source:BMC Med Genet;18(1):105, 2017 Sep 19.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. CASE PRESENTATION: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. CONCLUSIONS: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.
[Mh] Termos MeSH primário: Miosinas Cardíacas/genética
Variação Genética
Doenças Musculares/congênito
Cadeias Pesadas de Miosina/genética
[Mh] Termos MeSH secundário: Miopatias Distais/diagnóstico por imagem
Miopatias Distais/genética
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Músculo Esquelético/patologia
Doenças Musculares/diagnóstico por imagem
Doenças Musculares/genética
Mutação
Miopatias Congênitas Estruturais/diagnóstico por imagem
Miopatias Congênitas Estruturais/genética
Oftalmoplegia/diagnóstico por imagem
Oftalmoplegia/genética
Fenótipo
Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYH7 protein, human); 0 (Ryanodine Receptor Calcium Release Channel); EC 3.6.1.- (Cardiac Myosins); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0463-y


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[PMID]:28842446
[Au] Autor:Amburgey K; Tsuchiya E; de Chastonay S; Glueck M; Alverez R; Nguyen CT; Rutkowski A; Hornyak J; Beggs AH; Dowling JJ
[Ad] Endereço:From the Division of Neurology (K.A., E.T., C.-T.N., J.J.D.) and Program for Genetics and Genome Biology (E.T., J.J.D.), Hospital for Sick Children; Departments of Paediatrics (K.A., J.J.D.), Computer Science (M.G.), and Molecular Genetics (J.J.D.), University of Toronto, Ontario, Canada; Cure CMD (
[Ti] Título:A natural history study of X-linked myotubular myopathy.
[So] Source:Neurology;89(13):1355-1364, 2017 Sep 26.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To define the natural history of X-linked myotubular myopathy (MTM). METHODS: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). RESULTS: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non-muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. CONCLUSIONS: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention.
[Mh] Termos MeSH primário: Miopatias Congênitas Estruturais/epidemiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Comorbidade
Efeitos Psicossociais da Doença
Estudos Transversais
Seres Humanos
Incidência
Lactente
Recém-Nascido
Internet
Transtornos de Aprendizagem/epidemiologia
Transtornos de Aprendizagem/genética
Transtornos de Aprendizagem/fisiopatologia
Estudos Longitudinais
Masculino
Miopatias Congênitas Estruturais/genética
Miopatias Congênitas Estruturais/fisiopatologia
Miopatias Congênitas Estruturais/terapia
Estudos Prospectivos
Insuficiência Respiratória/mortalidade
Inquéritos e Questionários
Análise de Sobrevida
Telefone
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000004415


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[PMID]:28838934
[Au] Autor:Feingold B; Mahle WT; Auerbach S; Clemens P; Domenighetti AA; Jefferies JL; Judge DP; Lal AK; Markham LW; Parks WJ; Tsuda T; Wang PJ; Yoo SJ; American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council
[Ti] Título:Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association.
[So] Source:Circulation;136(13):e200-e231, 2017 Sep 26.
[Is] ISSN:1524-4539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
[Mh] Termos MeSH primário: Cardiomiopatias/diagnóstico
Doenças Musculares/diagnóstico
Doenças Neuromusculares/diagnóstico
[Mh] Termos MeSH secundário: American Heart Association
Síndrome de Barth/diagnóstico
Síndrome de Barth/genética
Síndrome de Barth/metabolismo
Síndrome de Barth/patologia
Cardiomiopatias/complicações
Cardiomiopatias/patologia
Ataxia de Friedreich/diagnóstico
Ataxia de Friedreich/metabolismo
Ataxia de Friedreich/patologia
Seres Humanos
Doenças Musculares/metabolismo
Doenças Musculares/patologia
Distrofia Muscular do Cíngulo dos Membros/diagnóstico
Distrofia Muscular do Cíngulo dos Membros/metabolismo
Distrofia Muscular do Cíngulo dos Membros/patologia
Distrofia Muscular de Duchenne/diagnóstico
Distrofia Muscular de Duchenne/metabolismo
Distrofia Muscular de Duchenne/patologia
Distrofia Muscular de Emery-Dreifuss/diagnóstico
Distrofia Muscular de Emery-Dreifuss/metabolismo
Distrofia Muscular de Emery-Dreifuss/patologia
Miopatias Congênitas Estruturais/diagnóstico
Miopatias Congênitas Estruturais/genética
Miopatias Congênitas Estruturais/metabolismo
Miopatias Congênitas Estruturais/patologia
Distrofia Miotônica/diagnóstico
Distrofia Miotônica/metabolismo
Distrofia Miotônica/patologia
Doenças Neuromusculares/complicações
Doenças Neuromusculares/patologia
Fatores de Risco
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; PRACTICE GUIDELINE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE
[do] DOI:10.1161/CIR.0000000000000526


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[PMID]:28370029
[Au] Autor:Elverman M; Goddard MA; Mack D; Snyder JM; Lawlor MW; Meng H; Beggs AH; Buj-Bello A; Poulard K; Marsh AP; Grange RW; Kelly VE; Childers MK
[Ad] Endereço:Department of Rehabilitation Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
[Ti] Título:Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.
[So] Source:Muscle Nerve;56(5):943-953, 2017 Nov.
[Is] ISSN:1097-4598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. METHODS: We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression. RESULTS: Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength. CONCLUSIONS: AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017.
[Mh] Termos MeSH primário: Terapia Genética
Miopatias Congênitas Estruturais/terapia
Proteínas Tirosina Fosfatases não Receptoras/uso terapêutico
[Mh] Termos MeSH secundário: Adenosina Trifosfatases/metabolismo
Animais
Dependovirus/genética
Modelos Animais de Doenças
Cães
Feminino
Transtornos Neurológicos da Marcha/etiologia
Glucuronidase/genética
Glucuronidase/metabolismo
Seres Humanos
Estudos Longitudinais
Microscopia Eletrônica
Músculo Esquelético/patologia
Músculo Esquelético/ultraestrutura
Mutação/genética
Miopatias Congênitas Estruturais/complicações
Miopatias Congênitas Estruturais/genética
Miopatias Congênitas Estruturais/veterinária
NAD/metabolismo
Exame Neurológico
Proteínas Tirosina Fosfatases não Receptoras/genética
Transtornos Respiratórios/etiologia
Transdução Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0U46U6E8UK (NAD); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor); EC 3.1.3.48 (myotubularin); EC 3.2.1.31 (Glucuronidase); EC 3.6.1.- (Adenosine Triphosphatases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1002/mus.25658


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[PMID]:28237839
[Au] Autor:Mack DL; Poulard K; Goddard MA; Latournerie V; Snyder JM; Grange RW; Elverman MR; Denard J; Veron P; Buscara L; Le Bec C; Hogrel JY; Brezovec AG; Meng H; Yang L; Liu F; O'Callaghan M; Gopal N; Kelly VE; Smith BK; Strande JL; Mavilio F; Beggs AH; Mingozzi F; Lawlor MW; Buj-Bello A; Childers MK
[Ad] Endereço:Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA; Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98107, USA.
[Ti] Título:Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs.
[So] Source:Mol Ther;25(4):839-854, 2017 Apr 05.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.
[Mh] Termos MeSH primário: Dependovirus/genética
Terapia Genética
Vetores Genéticos/genética
Músculo Esquelético/metabolismo
Miopatias Congênitas Estruturais/genética
[Mh] Termos MeSH secundário: Animais
Biópsia
Dependovirus/classificação
Modelos Animais de Doenças
Progressão da Doença
Cães
Marcha
Expressão Gênica
Terapia Genética/efeitos adversos
Terapia Genética/métodos
Vetores Genéticos/administração & dosagem
Vetores Genéticos/efeitos adversos
Vetores Genéticos/farmacocinética
Imunidade Celular
Imunidade Humoral
Estimativa de Kaplan-Meier
Força Muscular
Músculo Esquelético/patologia
Músculo Esquelético/fisiopatologia
Músculo Esquelético/ultraestrutura
Miopatias Congênitas Estruturais/diagnóstico
Miopatias Congênitas Estruturais/mortalidade
Miopatias Congênitas Estruturais/terapia
Proteínas Tirosina Fosfatases não Receptoras/genética
Recuperação de Função Fisiológica
Reflexo
Testes de Função Respiratória
Distribuição Tecidual
Transgenes/genética
Transgenes/imunologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor); EC 3.1.3.48 (myotubularin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170227
[St] Status:MEDLINE


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[PMID]:28220527
[Au] Autor:Lornage X; Malfatti E; Chéraud C; Schneider R; Biancalana V; Cuisset JM; Garibaldi M; Eymard B; Fardeau M; Boland A; Deleuze JF; Thompson J; Carlier RY; Böhm J; Romero NB; Laporte J
[Ad] Endereço:Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.
[Ti] Título:Recessive MYPN mutations cause cap myopathy with occasional nemaline rods.
[So] Source:Ann Neurol;81(3):467-473, 2017 Mar.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
[Mh] Termos MeSH primário: Proteínas Musculares/genética
Miopatias Congênitas Estruturais/genética
[Mh] Termos MeSH secundário: Adulto
Consanguinidade
Exoma
Feminino
Seres Humanos
Masculino
Mutação
Miopatias Congênitas Estruturais/patologia
Miopatias Congênitas Estruturais/fisiopatologia
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYPN protein, human); 0 (Muscle Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24900


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[PMID]:28127073
[Au] Autor:Aden P; Annexstad EJ; Lien E; Tajsic JM; Mjellem N; Rasmussen M
[Ad] Endereço:Seksjon for nevrohabilitering Oslo universitetssykehus.
[Ti] Título:[Juvenile-onset muscular diseases].
[Ti] Título:Muskelsykdommer med debut i barnealder..
[So] Source:Tidsskr Nor Laegeforen;137(2):108-111, 2017 Jan.
[Is] ISSN:0807-7096
[Cp] País de publicação:Norway
[La] Idioma:nor
[Ab] Resumo:Children with muscular diseases constitute an important group in paediatric neurology. Some of the conditions are very serious and require extensive interdisciplinary treatment and facilitation. There is some degree of optimism regarding the possibility of causal treatment in some of the conditions.
[Mh] Termos MeSH primário: Distrofias Musculares
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Seres Humanos
Lactente
Distrofias Musculares/congênito
Distrofias Musculares/diagnóstico
Distrofias Musculares/terapia
Miastenia Gravis/diagnóstico
Miastenia Gravis/terapia
Síndromes Miastênicas Congênitas/diagnóstico
Síndromes Miastênicas Congênitas/terapia
Miopatias Congênitas Estruturais/diagnóstico
Miopatias Congênitas Estruturais/terapia
Medula Espinal/anatomia & histologia
Medula Espinal/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.4045/tidsskr.16.0623


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[PMID]:28104788
[Au] Autor:Berger J; Berger S; Li M; Currie PD
[Ad] Endereço:Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
[Ti] Título:Myo18b is essential for sarcomere assembly in fast skeletal muscle.
[So] Source:Hum Mol Genet;26(6):1146-1156, 2017 Mar 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Congenital myopathies are muscle degenerative disorders with a broad clinical spectrum. A number of myopathies have been associated with molecular defects within sarcomeres, the force-generating component of the muscle cell. Whereas the highly regular organization of the myofibril has been studied in detail, in vivo assembly of sarcomeres remains a poorly understood process. Therefore, a more detailed knowledge of sarcomere assembly is crucial to better understand the pathogenic mechanisms within myopathies. Recently, mutations in myosin XVIIIB (MYO18B) have been associated with cases of myopathies, although the underlying mechanism for the resulting pathology remains to be defined. To analyze the role of myosin XVIIIB in skeletal muscle disease, zebrafish mutants for myo18b were generated. Full loss of myo18b function results in a complete lack of sarcomeric structure, revealing a highly surprising and essential role for myo18b in sarcomere assembly. Importantly, scattered thin and thick filaments assemble throughout the sarcoplasm; but fail to organize into recognizable sarcomeric structures in myo18b null mutants. In myo18b partial loss-of-function mutants sarcomeric structures are assembled, but thin and thick filaments remain misaligned within these structures. These observations suggest a novel model of sarcomere assembly where Myo18b coordinates the integration of preformed thick and thin filaments into the sarcomere. Disruption of this highly coordinated process results in a block in sarcomere biogenesis and the onset of myopathic pathology.
[Mh] Termos MeSH primário: Músculo Esquelético/metabolismo
Miopatias Congênitas Estruturais/genética
Miosinas/genética
Sarcômeros/genética
Proteínas Supressoras de Tumor/genética
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/genética
Citoesqueleto de Actina/metabolismo
Animais
Seres Humanos
Músculo Esquelético/patologia
Proteínas Mutantes/genética
Miopatias Congênitas Estruturais/patologia
Miosinas/biossíntese
Sarcômeros/metabolismo
Sarcômeros/patologia
Proteínas Supressoras de Tumor/biossíntese
Peixe-Zebra/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYO18B protein, human); 0 (Mutant Proteins); 0 (Tumor Suppressor Proteins); EC 3.6.4.1 (Myosins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx025


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[PMID]:28007904
[Au] Autor:Bachmann C; Jungbluth H; Muntoni F; Manzur AY; Zorzato F; Treves S
[Ad] Endereço:Departments of Biomedicine and Anesthesia, Basel University Hospital, Basel University, Basel, Switzerland.
[Ti] Título:Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations.
[So] Source:Hum Mol Genet;26(2):320-332, 2017 Jan 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients.
[Mh] Termos MeSH primário: Histona Desacetilases/genética
Músculo Esquelético/metabolismo
Miopatias Congênitas Estruturais/genética
Proteínas Tirosina Fosfatases não Receptoras/genética
Proteínas Repressoras/genética
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Mh] Termos MeSH secundário: Animais
Biópsia
Cálcio/metabolismo
Criança
Pré-Escolar
Feminino
Regulação da Expressão Gênica
Histona Desacetilases/biossíntese
Seres Humanos
Lactente
Recém-Nascido
Masculino
Camundongos
Camundongos Knockout
MicroRNAs/genética
Músculo Esquelético/patologia
Mutação
Miopatias Congênitas Estruturais/metabolismo
Miopatias Congênitas Estruturais/patologia
Proteínas Repressoras/biossíntese
Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MicroRNAs); 0 (Repressor Proteins); 0 (Ryanodine Receptor Calcium Release Channel); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor); EC 3.1.3.48 (myotubularin); EC 3.5.1.98 (HDAC4 protein, human); EC 3.5.1.98 (Histone Deacetylases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161224
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw388


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[PMID]:27939133
[Au] Autor:Walmsley GL; Blot S; Venner K; Sewry C; Laporte J; Blondelle J; Barthélémy I; Maurer M; Blanchard-Gutton N; Pilot-Storck F; Tiret L; Piercy RJ
[Ad] Endereço:Comparative Neuromuscular Diseases Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London, United Kingdom. Electronic address: glw22@liv.ac.uk.
[Ti] Título:Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems.
[So] Source:Am J Pathol;187(2):441-456, 2017 Feb.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes.
[Mh] Termos MeSH primário: Músculo Esquelético/patologia
Miopatias Congênitas Estruturais/patologia
Proteínas Tirosina Fosfatases/genética
[Mh] Termos MeSH secundário: Animais
Membrana Celular/patologia
Modelos Animais de Doenças
Cães
Imuno-Histoquímica
Microscopia Confocal
Microscopia Eletrônica de Transmissão
Miopatias Congênitas Estruturais/genética
Miopatias Congênitas Estruturais/metabolismo
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.48 (Protein Tyrosine Phosphatases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE



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