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1.
Brain Dev ; 43(3): 440-447, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33277141

RESUMO

BACKGROUND: Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases. SUBJECTS AND METHODS: The influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy. RESULTS: A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions. CONCLUSION: Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.


Assuntos
Creatina Quinase/sangue , Infecções/enzimologia , Síndrome de Walker-Warburg/sangue , Síndrome de Walker-Warburg/enzimologia , Adolescente , Proteína C-Reativa/metabolismo , Criança , Feminino , Febre , Humanos , Infecções/sangue , Masculino , Adulto Jovem
2.
J Biol Chem ; 290(16): 10256-73, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25737452

RESUMO

Protein O-mannosylation is a glycan modification that is required for normal nervous system development and function. Mutations in genes involved in protein O-mannosyl glycosylation give rise to a group of neurodevelopmental disorders known as congenital muscular dystrophies (CMDs) with associated CNS abnormalities. Our previous work demonstrated that receptor protein-tyrosine phosphatase ζ (RPTPζ)/phosphacan is hypoglycosylated in a mouse model of one of these CMDs, known as muscle-eye-brain disease, a disorder that is caused by loss of an enzyme (protein O-mannose ß-1,2-N-acetylglucosaminyltransferase 1) that modifies O-mannosyl glycans. In addition, monoclonal antibodies Cat-315 and 3F8 were demonstrated to detect O-mannosyl glycan modifications on RPTPζ/phosphacan. Here, we show that O-mannosyl glycan epitopes recognized by these antibodies define biochemically distinct glycoforms of RPTPζ/phosphacan and that these glycoforms differentially decorate the surface of distinct populations of neural cells. To provide a further structural basis for immunochemically based glycoform differences, we characterized the O-linked glycan heterogeneity of RPTPζ/phosphacan in the early postnatal mouse brain by multidimensional mass spectrometry. Structural characterization of the O-linked glycans released from purified RPTPζ/phosphacan demonstrated that this protein is a significant substrate for protein O-mannosylation and led to the identification of several novel O-mannose-linked glycan structures, including sulfo-N-acetyllactosamine containing modifications. Taken together, our results suggest that specific glycan modifications may tailor the function of this protein to the unique needs of specific cells. Furthermore, their absence in CMDs suggests that hypoglycosylation of RPTPζ/phosphacan may have different functional consequences in neurons and glia.


Assuntos
Encéfalo/enzimologia , N-Acetilglucosaminiltransferases/genética , Neuroglia/enzimologia , Neurônios/enzimologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/química , Síndrome de Walker-Warburg/genética , Amino Açúcares/química , Amino Açúcares/metabolismo , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/química , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Sequência de Carboidratos , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Glicosilação , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Manose/química , Manose/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , N-Acetilglucosaminiltransferases/deficiência , Neuroglia/patologia , Neurônios/patologia , Especificidade de Órgãos , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Transdução de Sinais , Síndrome de Walker-Warburg/enzimologia , Síndrome de Walker-Warburg/patologia
3.
J Neurol Sci ; 318(1-2): 45-50, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22554691

RESUMO

Congenital muscular dystrophies due to defects in genes encoding proteins involved in α-dystroglycan (α-DG) glycosylation are a heterogeneous group of muscle disorders variably associated with central nervous system and eye abnormalities. One of the more severe is muscle-eye-brain disease (MEB). Mutations in genes coding for proven or putative glycosyltransferases (POMT1, POMT2, POMGnT1, fukutin, FKRP, and LARGE), the DPM3 gene encoding a DOL-P-Man synthase subunit, and the DAG1 gene encoding α-dystroglycan, have been associated with altered α-DG glycosylation. We report new POMGnT1 mutations and evaluate protein expression in 3 patients and 2 foetuses with variably severe MEB features. We identify two new point mutations (c.643C>T, c.1863delC), one new intragenic rearrangement (deletion of exons 2-8), and a new intron retention (between exons 21 and 22) resulting from a known point mutation c.1895+1G>T. Our study provides further evidence that rearrangements of the POMGnT1 gene are relatively common. Importantly, if heterozygous, they can be missed on standard genomic DNA sequencing. POMGNT1 protein analysis in 3 patients showed that the severity of the phenotype does not correlate with protein expression. Cerebral MRI is important for identifying MEB and α-dystroglycanopathy phenotypes in children and foetuses, and hence for directing the genetic analysis.


Assuntos
Predisposição Genética para Doença/genética , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Síndrome de Walker-Warburg/enzimologia , Síndrome de Walker-Warburg/genética , Adolescente , Criança , Pré-Escolar , Evolução Fatal , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/enzimologia , Doenças Fetais/genética , Rearranjo Gênico/genética , Humanos , Masculino , Fenótipo , Mutação Puntual/genética , Gravidez , Índice de Gravidade de Doença , Síndrome de Walker-Warburg/diagnóstico
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