RESUMO
Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.
Assuntos
Cofilina 2/genética , Doenças Musculares/patologia , Adolescente , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Cofilina 2/química , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Músculo Esquelético/patologia , Adulto JovemRESUMO
Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
Assuntos
Cardiomiopatia Hipertrófica/genética , Lisina-tRNA Ligase/genética , Doenças Mitocondriais/genética , Transtornos Psicomotores/genética , Adolescente , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Transporte de Elétrons/genética , Feminino , Predisposição Genética para Doença , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Mutação , Fenótipo , Transtornos Psicomotores/complicações , Transtornos Psicomotores/patologiaRESUMO
OBJECTIVES: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status. METHODS: Expression levels of IL-17, Foxp3, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-6, and transforming growth factor-ß (TGF-ß) were analyzed by real-time PCR in muscle biopsy samples from patients with DMD (n = 27) and juvenile dermatomyositis (JDM) (n = 8). Motor outcome of patients with DMD was evaluated by North Star Ambulatory Assessment score. RESULTS: In DMD, we found higher levels of IL-17 and lower levels of Foxp3 mRNA compared with those for a typical inflammatory myopathy, JDM. Moreover, the IL-17/Foxp3 ratio was higher in DMD than in JDM biopsy samples. IL-17 mRNA levels appeared to be related to the expression levels of other proinflammatory cytokines (TNF-α and MCP-1) and significantly associated with clinical outcome of patients. CONCLUSIONS: The association of IL-17 expression with levels of other inflammatory cytokines and with the clinical course of DMD suggests a possible pathogenic role of IL-17.
Assuntos
Interleucina-17/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Biópsia , Quimiocina CCL2/metabolismo , Criança , Pré-Escolar , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-6/metabolismo , Músculo Esquelético/patologia , Valores de Referência , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Work at high altitude (elevation equal to or greater than 3000 m above sea level) results in a physiological adaptation of the human organism to changing environmental conditions. The main problem related to the altitude is represented by the reduction of partial pressure of oxygen (hypoxia). Our study takes into consideration occupational risk factors: those related to physical environment of high altitude; those related to the worker; those related to the characteristics of the job. It is finally addressed the decision making process related to the formulation of the judgment of suitability for performance of work activities at high altitude. The health protocol proposed requires an accurate anamnestic investigation aimed at gathering information on pre-existing pathophysiological conditions that need, once identified, clinical and instrumental tests specific and targeted. These clinical protocols are analyzed and proposed for the main pathophysiologic conditions that pose a risk to health at high altitude.
Assuntos
Altitude , Exposição Ocupacional/efeitos adversos , Saúde Ocupacional , Vigilância da População , Humanos , Fatores de RiscoAssuntos
Toxoide Tetânico , Tétano/prevenção & controle , Vacinação/estatística & dados numéricos , Voluntários , Adolescente , Adulto , Idoso , Anticorpos/sangue , Feminino , Incêndios , Humanos , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in the lamin A/C gene (LMNA) have been associated with neuromuscular diseases and more complex syndromes, involving bone and adipose tissue. We report on a case of early onset myopathy due to a heterozygous LMNA mutation in exon 9, characterized by the presence of a marked number of cytoplasmic bodies with extensive myofibrillar abnormalities and Z-disk disruption in skeletal muscle. This case suggests there is a need to increase the list of genes to be screened in patients with myofibrillar myopathy.
Assuntos
Lamina Tipo A/genética , Doenças Musculares/genética , Mutação de Sentido Incorreto/genética , Miofibrilas/patologia , Criança , Análise Mutacional de DNA/métodos , Desmina/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Éxons , Feminino , Humanos , Imuno-Histoquímica/métodos , Doenças Musculares/metabolismo , Miofibrilas/metabolismo , Miofibrilas/ultraestruturaRESUMO
cGMP-phosphodiesterase (PDE) is a key component in visual phototransduction. Rod and cone photoreceptors each produce their unique cGMP-PDE subunits. The alpha' catalytic subunits are believed to be cone-specific. In this study, we report that transfection of the -132 to +139 sequence in the upstream region of the human alpha'-PDE gene fused to luciferase cDNA gives the highest level of reporter gene transcription in cultured retinoblastoma Y79 cells. Transgenic Xenopus laevis carrying this sequence fused to green fluorescent protein (GFP) expressed GFP in cones, suggesting a conserved regulatory mechanism for alpha'-PDE transcription in both human and frog.
Assuntos
Regulação da Expressão Gênica , Luz , Transdução de Sinais/genética , Transcrição Gênica , Vertebrados/genética , Animais , Animais Geneticamente Modificados , Sequência de Bases , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Imuno-Histoquímica , Xenopus laevisRESUMO
Eight unrelated Italian patients with the hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome were analyzed for mutations in the ORNT1 gene. Seven novel mutations were identified (Q89X, G27R, G190D, R275Q, c.861insG, c.164insA, and IVS5+1G-->A). Other previously described variants were a heterozygous deletion of a phenylalanine residue (F188del) in one allele and the R179X in two. The G27R mutation was carried by two patients. Analyses of ORNT1 mRNA in four patients showed that mutant alleles were stable and of the predicted size. The current study expands the spectrum of mutations in ORNT1 gene.
Assuntos
Citrulina/análogos & derivados , Citrulina/metabolismo , Hiperamonemia/genética , Erros Inatos do Metabolismo/genética , Mutação/genética , Ornitina/metabolismo , Proteínas/genética , Idade de Início , Alelos , Sistemas de Transporte de Aminoácidos Básicos , Sequência de Bases , Análise Mutacional de DNA , Éxons/genética , Feminino , Fibroblastos , Humanos , Hiperamonemia/epidemiologia , Hiperamonemia/patologia , Hiperamonemia/fisiopatologia , Recém-Nascido , Itália , Masculino , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Proteínas de Transporte da Membrana Mitocondrial , Linhagem , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SíndromeRESUMO
Drosophila ISWI, a highly conserved member of the SWI2/SNF2 family of ATPases, is the catalytic subunit of three chromatin-remodeling complexes: NURF, CHRAC, and ACF. To clarify the biological functions of ISWI, we generated and characterized null and dominant-negative ISWI mutations. We found that ISWI mutations affect both cell viability and gene expression during Drosophila development. ISWI mutations also cause striking alterations in the structure of the male X chromosome. The ISWI protein does not colocalize with RNA Pol II on salivary gland polytene chromosomes, suggesting a possible role for ISWI in transcriptional repression. These findings reveal novel functions for the ISWI ATPase and underscore its importance in chromatin remodeling in vivo.