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1.
J Paediatr Child Health ; 58(7): 1233-1237, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35411664

RESUMEN

AIM: To determine the characteristics of balance bike injuries. METHODS: This study retrospectively identified patients injured while riding a balance bike and treated at one paediatric emergency department in urban Japan, from February 2015 to July 2020. Data extracted were patient age and sex, circumstances and location of the injury occurrence, helmet use, adult supervision, injury type and body site, treatment and emergency department disposition. Based on these data and the balance bike manual instructions, cases were classified as correct and incorrect balance bike use. RESULTS: The study assessed 78 patients, age 2-6 years (median 3 years; 73% male). Of these 78 patients, 63 did not follow balance bike manual instructions (80.8%); 34 (43.6%) were injured while riding in prohibited places of use; 45 (57.7%) were injured in prohibited situations of use; and 37 (47.4%) were injured despite adult supervision. A total of 124 injuries were noted; the most common injured body site was the face (49 injuries, 39.5%), followed by the head (40 injuries, 32.3%). Most injuries were contusions and abrasions (65 injuries, 52.4%). More serious injuries were intensive care unit admission with intracerebral haemorrhage (1 patient) and lateral condyle fracture with surgical repair (1 patient). CONCLUSIONS: Most of the 78 balance bike injuries (76 patients) were mild; 2 were more severe and required intensive care unit admission or operation. Parents must be aware of the rules and instructions for balance bike use and ensure that their children can use the balance bike correctly.


Asunto(s)
Traumatismos en Atletas , Heridas y Lesiones , Adulto , Traumatismos en Atletas/epidemiología , Ciclismo/lesiones , Niño , Preescolar , Servicio de Urgencia en Hospital , Femenino , Dispositivos de Protección de la Cabeza , Hospitalización , Humanos , Masculino , Estudios Retrospectivos
2.
Mol Ther ; 28(4): 1133-1153, 2020 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-32087766

RESUMEN

Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Disferlina/química , Disferlina/metabolismo , Metformina/administración & dosificación , Músculo Esquelético/lesiones , Distrofia Muscular de Cinturas/tratamiento farmacológico , Animales , Línea Celular , Modelos Animales de Enfermedad , Disferlina/genética , Humanos , Rayos Láser/efectos adversos , Metformina/farmacología , Ratones , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/metabolismo , Mutación , Fosforilación , Dominios Proteicos , Sarcolema/metabolismo , Pez Cebra
3.
Am J Hum Genet ; 100(1): 169-178, 2017 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-28017374

RESUMEN

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.


Asunto(s)
Alelos , Progresión de la Enfermedad , Proteínas Musculares/genética , Mutación , Miopatías Nemalínicas/genética , Adulto , Edad de Inicio , Animales , Niño , Preescolar , Femenino , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Miopatías Nemalínicas/patología , Linaje
4.
Biochem Biophys Res Commun ; 512(1): 22-28, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-30853177

RESUMEN

The C-terminal Ig-domain of lamin A plays critical roles in cell function via interaction with proteins, DNA, and chromatin. Mutations in this domain are known to cause various diseases including Emery-Dreifuss muscular dystrophy (EDMD) and familial partial lipodystrophy (FPLD). Here we examined the biophysical and biochemical properties of mutant Ig-domains identified in patients with EDMD and FPLD. EDMD-related mutant Ig-domain showed decreased stability to heat and denaturant. This result was also confirmed by experiments using full-length mutant lamin A, although the decrease in melting temperature was much less than that of the mutant Ig-domain alone. The unstable EDMD Ig-domain disrupted the proper assembly of lamin A, resulting in abnormal paracrystal formation and decreased viscosity. In contrast, FPLD-related mutant Ig-domains were thermally stable, although they lost DNA binding function. Alanine substitution experiments revealed a functional domain of DNA binding in the Ig-domain. Thus, the overall biophysical property of Ig-domains is closely associated with clinical phenotype.


Asunto(s)
Lamina Tipo A/química , Distrofia Muscular de Emery-Dreifuss/metabolismo , Sustitución de Aminoácidos , Fenómenos Biofísicos , ADN/química , ADN/metabolismo , Humanos , Técnicas In Vitro , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/metabolismo , Microscopía Electrónica de Transmisión , Modelos Moleculares , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Dominios Proteicos , Estabilidad Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
5.
Pathol Int ; 69(8): 496-501, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31276279

RESUMEN

Pathological diagnosis of dermal melanocytic tumors is often problematic owing to histological resemblance. Recently, cutaneous melanocytoma with CRTC1-TRIM11 (CMCT) was added to this category. However, only six cases have been reported so far. We herein present a case of a 77-year-old Japanese man with CMCT. The patient presented a nodule in the right thigh and underwent surgical resection. Histological examination indicated a well-demarcated 6 × 5 mm-sized tumor nodule in the dermis and subcutis. The tumor was amelanotic, consisting of uniform nests and fascicles of spindled, or epithelioid cells. The melanocytic nature was evident by immunohistochemistry. The CRTC1-TRIM11 fusion was detected by TRIM11 immunostaining, chromogenic in situ hybridization, and RT-PCR/direct sequencing. He has been free from the tumor for 1 year after additional resection. The main differential diagnosis of CMCT includes primary and metastatic dermal malignant melanomas (MM) and dermal/subcutaneous clear cell sarcoma (CCS). Additionally, histological overlap with paraganglioma-like dermal melanocytic tumor was considered. Although some investigators argue that CMCT is a variant of CCS, we think it should be separated from CCS, and subcutaneous/dermal CCS should be confined to tumors with EWSR1-ATF1/ CREB1 fusion. However, longer follow-up and more case studies are needed for revealing the true prognosis of CMCT.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Melanoma/diagnóstico , Proteínas de Fusión Oncogénica/metabolismo , Sarcoma de Células Claras/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Factores de Transcripción/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Anciano , Biomarcadores de Tumor/genética , Diagnóstico Diferencial , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patología , Proteínas de Fusión Oncogénica/genética , Sarcoma de Células Claras/metabolismo , Sarcoma de Células Claras/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Melanoma Cutáneo Maligno
6.
Hum Mol Genet ; 24(3): 637-48, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25227914

RESUMEN

The store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel is activated by diminished luminal Ca(2+) levels in the endoplasmic reticulum and sarcoplasmic reticulum (SR), and constitutes one of the major Ca(2+) entry pathways in various tissues. Tubular aggregates (TAs) are abnormal structures in the skeletal muscle, and although their mechanism of formation has not been clarified, altered Ca(2+) homeostasis related to a disordered SR is suggested to be one of the main contributing factors. TA myopathy is a hereditary muscle disorder that is pathologically characterized by the presence of TAs. Recently, dominant mutations in the STIM1 gene, encoding a Ca(2+) sensor that controls CRAC channels, have been identified to cause tubular aggregate myopathy (TAM). Here, we identified heterozygous missense mutations in the ORAI1 gene, encoding the CRAC channel itself, in three families affected by dominantly inherited TAM with hypocalcemia. Skeletal myotubes from an affected individual and HEK293 cells expressing mutated ORAI1 proteins displayed spontaneous extracellular Ca(2+) entry into cells without diminishment of luminal Ca(2+) or the association with STIM1. Our results indicate that STIM1-independent activation of CRAC channels induced by dominant mutations in ORAI1 cause altered Ca(2+) homeostasis, resulting in TAM with hypocalcemia.


Asunto(s)
Canales de Calcio/genética , Hipocalcemia/genética , Fibras Musculares Esqueléticas/patología , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Adulto , Calcio/metabolismo , Canales de Calcio/metabolismo , Niño , Preescolar , Células HEK293 , Heterocigoto , Humanos , Masculino , Fibras Musculares Esqueléticas/metabolismo , Mutación Missense , Miopatías Estructurales Congénitas/complicaciones , Proteína ORAI1 , Linaje , Molécula de Interacción Estromal 1
7.
J Virol ; 90(1): 300-7, 2016 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-26468521

RESUMEN

UNLABELLED: Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7:e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b(+) F4/80(+) CD11c(-) CD206(+) (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-α. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages. IMPORTANCE: HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment.


Asunto(s)
Hepacivirus/inmunología , Hepatitis C Crónica/patología , Macrófagos/inmunología , Macrófagos/virología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hepacivirus/genética , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Interleucina-6/metabolismo , Ratones Transgénicos , Factor de Necrosis Tumoral alfa/metabolismo
8.
Proc Natl Acad Sci U S A ; 111(10): 3811-6, 2014 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-24567387

RESUMEN

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.


Asunto(s)
Cardiomegalia/metabolismo , Caveolas/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Musculares/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Animales , Western Blotting , Cartilla de ADN/genética , Ecocardiografía , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Proteínas Musculares/genética , Miocitos Cardíacos/metabolismo , Interferencia de ARN , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
Am J Hum Genet ; 93(6): 1108-17, 2013 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-24268659

RESUMEN

Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM.


Asunto(s)
Mutación , Miofibrillas/metabolismo , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/metabolismo , Dominios y Motivos de Interacción de Proteínas , Proteínas/genética , Transducción de Señal , Ubiquitinación , Adolescente , Animales , Niño , Preescolar , Proteínas del Citoesqueleto , Resultado Fatal , Femenino , Expresión Génica , Orden Génico , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Modelos Moleculares , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Miopatías Nemalínicas/diagnóstico , Conformación Proteica , Proteínas/química , Pez Cebra
10.
Am J Hum Genet ; 93(1): 6-18, 2013 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-23746549

RESUMEN

Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.


Asunto(s)
Proteínas Musculares/metabolismo , Músculo Esquelético/patología , Mutación Missense , Miopatías Nemalínicas/genética , Sustitución de Aminoácidos , Animales , Pueblo Asiatico/genética , Estudios de Cohortes , Mutación del Sistema de Lectura , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Proteínas Musculares/genética , Miopatías Nemalínicas/etnología , Miopatías Nemalínicas/patología , Linaje , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Pez Cebra/genética
11.
Muscle Nerve ; 53(3): 394-401, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26088049

RESUMEN

INTRODUCTION: We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. METHODS: Subjects included 48 patients who underwent respiratory evaluation (n = 47), electrocardiography (n = 46), and echocardiography (n = 23). RESULTS: Of the 47 patients, 10 had reduced percent forced vital capacity (%FVC), and 4 required non-invasive positive pressure ventilation. %FVC was significantly correlated with disease duration, and mean %FVC was significantly lower in non-ambulatory patients, as well as in those aged ≥65 years with normal creatine kinase levels. On electrocardiography, QRS complex duration was prolonged in 19 patients, although no significant association with age, disease duration, or respiratory function was found. Echocardiography indicated no left ventricular dysfunction in any patient. Histopathology of autopsied cases revealed mild cardiomyopathy and moderate diaphragm involvement. CONCLUSION: Patients with dysferlinopathy may develop severe respiratory failure and latent cardiac dysfunction. Both respiratory and cardiac function should be monitored diligently.


Asunto(s)
Cardiopatías/etiología , Distrofia Muscular de Cinturas/complicaciones , Trastornos Respiratorios/etiología , Adulto , Factores de Edad , Anciano , Autopsia , Creatina Quinasa/sangre , Disferlina , Electrocardiografía , Femenino , Cardiopatías/diagnóstico , Humanos , Japón , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas Musculares/genética , Distrofia Muscular de Cinturas/sangre , Distrofia Muscular de Cinturas/genética , Mutación/genética , Trastornos Respiratorios/diagnóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Capacidad Vital , Adulto Joven
12.
Nature ; 464(7293): 1313-9, 2010 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-20357764

RESUMEN

Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/metabolismo , Calcio/metabolismo , Mitocondrias/metabolismo , Receptores de Adiponectina/metabolismo , Sirtuina 1/metabolismo , Transactivadores/metabolismo , Animales , Señalización del Calcio , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Línea Celular , Glucosa/metabolismo , Homeostasis , Insulina/metabolismo , Resistencia a la Insulina , Ratones , Células Musculares/citología , Células Musculares/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Oocitos/metabolismo , Estrés Oxidativo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Condicionamiento Físico Animal , Receptores de Adiponectina/deficiencia , Factores de Transcripción , Xenopus laevis
13.
Neuropathology ; 36(6): 561-565, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27145725

RESUMEN

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is characterized clinically by cardiomyopathy, myopathy and intellectual disability in boys. Because Danon disease is inherited in an X-linked dominant fashion, males are more severely affected than females, who usually have only cardiomyopathy without myopathy or intellectual disability; moreover, the onset of symptoms in females is usually in adulthood. We describe a girl with Danon disease who presented with hypertrophic cardiomyopathy and Wolff-Parkinson-White (WPW) syndrome at 12 years of age. Subsequently, she showed signs of mild learning disability and intellectual disability on psychological examinations. She had a de novo novel mutation in the LAMP-2 gene and harbored an identical c.749C > A (p.Ser250X) variant, resulting in a stop codon in exon 6. She showed decreased, but not completely absent LAMP-2 expression on immunohistochemical and Western blot analyses of a skeletal muscle biopsy specimen, which has been suggested to be caused by a 50% reduction in LAMP-2 expression (LAMP-2 haploinsufficiency) in female patients with Danon disease caused by a heterozygous null mutation. To our knowledge, our patient is one of the youngest female patients to have been given a diagnosis of Danon disease. In addition, this is the first documented case in a girl that was clearly associated with intellectual disability, which is very rare in females with Danon disease. Our findings suggest that studies of female patients with Danon disease can extend our understanding of the clinical features of this rare disease.


Asunto(s)
Cardiomiopatías/etiología , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Discapacidad Intelectual/etiología , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Mutación , Adolescente , Femenino , Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Enfermedad por Depósito de Glucógeno de Tipo IIb/patología , Enfermedad por Depósito de Glucógeno de Tipo IIb/psicología , Humanos , Músculo Esquelético/patología , Síndrome de Wolff-Parkinson-White/complicaciones
14.
Hum Mutat ; 36(4): 443-53, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25615407

RESUMEN

Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N < 10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as FSHD1. FSHD-like phenotypes may also appear in the absence of D4Z4 copy-number reduction. Variants of the SMCHD1 gene have been reported to associate with D4Z4 hypomethylation in DUX4-compatible haplotypes, thus defining FSHD2. Recently, mice carrying a muscle-specific knock-out of the protocadherin gene Fat1 or its constitutive hypomorphic allele were shown to develop muscular and nonmuscular defects mimicking human FSHD. Here, we report FAT1 variants in a group of patients presenting with neuromuscular symptoms reminiscent of FSHD. The patients do not carry D4Z4 copy-number reduction, 4q hypomethylation, or SMCHD1 variants. However, abnormal splicing of the FAT1 transcript is predicted for all identified variants. To determine their pathogenicity, we elaborated a minigene approach coupled to an antisense oligonucleotide (AON) assay. In vitro, four out of five selected variants induced partial or complete alteration of splicing by creating new splice sites or modifying splicing regulators. AONs confirmed these effects. Altered transcripts may affect FAT1 protein interactions or stability. Altogether, our data suggest that defective FAT1 is associated with an FSHD-like phenotype.


Asunto(s)
Cadherinas/genética , Cromosomas Humanos Par 4 , Variación Genética , Distrofia Muscular Facioescapulohumeral/diagnóstico , Distrofia Muscular Facioescapulohumeral/genética , Fenotipo , Adolescente , Adulto , Anciano , Alelos , Empalme Alternativo , Niño , Preescolar , Metilación de ADN , Exones , Expresión Génica , Genes Reporteros , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Adulto Joven
15.
J Neurol Neurosurg Psychiatry ; 86(5): 483-9, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25253871

RESUMEN

BACKGROUND: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown. OBJECTIVE: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs). METHODS: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM. RESULTS: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort. CONCLUSIONS: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.


Asunto(s)
Citoplasma/patología , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/metabolismo , Proteínas Musculares/metabolismo , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/metabolismo , Agregación Patológica de Proteínas/metabolismo , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/metabolismo , Adulto , Anciano , Biomarcadores/metabolismo , Conectina/genética , Citoplasma/ultraestructura , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Musculares/genética , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/patología , Sensibilidad y Especificidad
16.
Brain ; 137(Pt 10): 2670-9, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25062695

RESUMEN

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6'-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6'-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6'-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6'-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6'-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6'-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.


Asunto(s)
Miopatías Distales/tratamiento farmacológico , Lactosa/análogos & derivados , Envejecimiento/patología , Péptidos beta-Amiloides/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Células Cultivadas , Creatina Quinasa/metabolismo , Modelos Animales de Enfermedad , Miopatías Distales/patología , Ensayo de Inmunoadsorción Enzimática , Hexosaminas/uso terapéutico , Lactosa/efectos adversos , Lactosa/farmacocinética , Lactosa/uso terapéutico , Ratones , Contracción Muscular/fisiología , Músculo Esquelético/patología , Mutación/genética , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Ácido N-Acetilneuramínico/uso terapéutico , Fragmentos de Péptidos/metabolismo , Fenotipo
17.
Am J Hum Genet ; 88(6): 845-851, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21665002

RESUMEN

Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.


Asunto(s)
Colina Quinasa/genética , Mitocondrias Musculares/patología , Distrofias Musculares/congénito , Distrofias Musculares/patología , Fosfatidilcolinas/biosíntesis , Adolescente , Niño , Preescolar , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Mitocondrias Musculares/genética , Distrofias Musculares/genética , Mutación , Linaje , Fosfatidilcolinas/genética , Polimorfismo Genético , Adulto Joven
18.
J Neurol Neurosurg Psychiatry ; 85(8): 914-7, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24027297

RESUMEN

BACKGROUND: GNE myopathy (also called distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy) is an autosomal recessive myopathy characterised by skeletal muscle atrophy and weakness that preferentially involve the distal muscles. It is caused by mutations in the gene encoding a key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). METHODS: We analysed the GNE gene in 212 Japanese GNE myopathy patients. A retrospective medical record review was carried out to explore genotype-phenotype correlation. RESULTS: Sixty-three different mutations including 25 novel mutations were identified: 50 missense mutations, 2 nonsense mutations, 1 insertion, 4 deletions, 5 intronic mutations and 1 single exon deletion. The most frequent mutation in the Japanese population is c.1714G>C (p.Val572Leu), which accounts for 48.3% of total alleles. Homozygosity for this mutation results in more severe phenotypes with earlier onset and faster progression of the disease. In contrast, the second most common mutation, c.527A>T (p.Asp176Val), seems to be a mild mutation as the onset of the disease is much later in the compound heterozygotes with this mutation and c.1714G>C than the patients homozygous for c.1714G>C. Although the allele frequency is 22.4%, there are only three homozygotes for c.527A>T, raising a possibility that a significant number of c.527A>T homozygotes may not develop an apparent disease. CONCLUSIONS: Here, we report the mutation profile of the GNE gene in 212 Japanese GNE myopathy patients, which is the largest single-ethnic cohort for this ultra-orphan disease. We confirmed the clinical difference between mutation groups. However, we should note that the statistical summary cannot predict clinical course of every patient.


Asunto(s)
Análisis Mutacional de ADN , Miopatías Distales/genética , Adulto , Edad de Inicio , Alelos , Carbohidrato Epimerasas/genética , ADN/genética , Dermatoglifia del ADN , Miopatías Distales/patología , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Mutación , Fenotipo , Estudios Retrospectivos , Adulto Joven
19.
Artículo en Inglés | MEDLINE | ID: mdl-38724872

RESUMEN

The presence of nuclear architectural abnormalities is a hallmark of the nuclear envelopathies, which are a group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations in the lamin A/C gene cause several diseases, named laminopathies, including muscular dystrophies, progeria syndromes, and lipodystrophy. A mouse model carrying with the LmnaH222P/H222P mutation (H222P) was shown to develop severe cardiomyopathy but only mild skeletal myopathy, although abnormal nuclei were observed in their striated muscle. In this report, we analyzed the abnormal-shaped nuclei in myoblasts and myotubes isolated from skeletal muscle of H222P mice, and evaluated the expression of nuclear envelope proteins in these abnormal myonuclei. Primary skeletal muscle cells from H222P mice proliferated and efficiently differentiated into myotubes in vitro, similarly to those from wild-type mice. During cell proliferation, few abnormal-shaped nuclei were detected; however, numerous markedly abnormal myonuclei were observed in myotubes from H222P mice on days 5 and 7 of differentiation. Time-lapse observation demonstrated that myonuclei with a normal shape maintained their normal shape, whereas abnormal-shaped myonuclei remained abnormal for at least 48 h during differentiation. Among the abnormal-shaped myonuclei, 65% had a bleb with a string structure, and 35% were severely deformed. The area and nuclear contents of the nuclear blebs were relatively stable, whereas the myocytes with nuclear blebs were actively fused within primary myotubes. Although myonuclei were markedly deformed, the deposition of DNA damage marker (γH2AX) or apoptotic marker staining was rarely observed. Localizations of lamin A/C and emerin were maintained within the blebs, strings, and severely deformed regions of myonuclei; however, lamin B1, nesprin-1, and a nuclear pore complex protein were absent in these abnormal regions. These results demonstrate that nuclear membranes from H222P skeletal muscle cells do not rupture and are resistant to DNA damage, despite these marked morphological changes.

20.
Dev Biol ; 361(1): 79-89, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22020047

RESUMEN

Filamin C is an actin-crosslinking protein that is specifically expressed in cardiac and skeletal muscles. Although mutations in the filamin C gene cause human myopathy with cardiac involvement, the function of filamin C in vivo is not yet fully understood. Here we report a medaka mutant, zacro (zac), that displayed an enlarged heart, caused by rupture of the myocardiac wall, and progressive skeletal muscle degeneration in late embryonic stages. We identified zac to be a homozygous nonsense mutation in the filamin C (flnc) gene. The medaka filamin C protein was found to be localized at myotendinous junctions, sarcolemma, and Z-disks in skeletal muscle, and at intercalated disks in the heart. zac embryos showed prominent myofibrillar degeneration at myotendinous junctions, detachment of myofibrils from sarcolemma and intercalated disks, and focal Z-disk destruction. Importantly, the expression of γ-actin, which we observed to have a strong subcellular localization at myotendinous junctions, was specifically reduced in zac mutant myotomes. Inhibition of muscle contraction by anesthesia alleviated muscle degeneration in the zac mutant. These results suggest that filamin C plays an indispensable role in the maintenance of the structural integrity of cardiac and skeletal muscles for support against mechanical stress.


Asunto(s)
Cardiomegalia/genética , Proteínas Contráctiles/genética , Proteínas Contráctiles/metabolismo , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Músculo Esquelético/metabolismo , Trastornos Musculares Atróficos/genética , Miocardio/metabolismo , Oryzias/embriología , Actinas/metabolismo , Animales , Birrefringencia , Clonación Molecular , Codón sin Sentido/genética , Cartilla de ADN/genética , Filaminas , Técnica del Anticuerpo Fluorescente , Hibridación in Situ , Microscopía Electrónica de Transmisión , Oligonucleótidos Antisentido/genética , Oryzias/genética , Polimorfismo de Longitud del Fragmento de Restricción/genética , Sarcolema/patología
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