Assuntos
Otopatias/diagnóstico , Micoses/diagnóstico , Pseudallescheria , Doenças do Nervo Abducente/microbiologia , Idoso , Antibacterianos/uso terapêutico , Doenças do Sistema Nervoso Central/microbiologia , Erros de Diagnóstico , Otopatias/complicações , Otopatias/microbiologia , Diagnóstico Precoce , Doenças do Nervo Facial/microbiologia , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética , Masculino , Mastoidite/microbiologia , Micoses/complicações , Micoses/microbiologia , Doenças Raras , Tomografia Computadorizada por Raios X , Perfuração da Membrana Timpânica/microbiologiaRESUMO
Translation of extracellular hormonal input into cellular responses is often mediated by repetitive increases in cytosolic free Ca(2+) concentration ([Ca(2+) ]c ). Amplitude, duration and frequency of these so-called [Ca(2+) ]c oscillations then carry information about the nature and concentration of the extracellular signalling molecule. At present, there are different hypotheses concerning the induction and control of these oscillations. Here, we investigated the role of agonist-induced receptor phosphorylation in this process using Chinese hamster ovary cells stably expressing a variant of the cholecystokinin 1 receptor (CCK1R) lacking the four consensus sites for protein kinase C (PKC) phosphorylation and deficient in CCK-induced receptor phosphorylation (CCK1R-mt cells). In the presence of cholecystokinin-(26-33)-peptide amide (CCK-8), these cells displayed Ca(2+) oscillations with a much more pronounced bursting dynamics rather than the dominant spiking dynamics observed in Chinese hamster ovary cells stably expressing the wild-type CCK1R. The bursting behaviour returned to predominantly spiking behaviour following removal of extracellular Ca(2+) , suggesting that CCK-8-induced, PKC-mediated CCK1R phosphorylation inhibits Ca(2+) influx across the plasma membrane. To gain mechanistic insight into the underlying mechanism we developed a mathematical model able to reproduce the experimental observations. From the model we conclude that binding of CCK-8 to the CCK1R leads to activation of PKC which subsequently phosphorylates the receptor to inhibit the receptor-mediated influx of Ca(2+) across the plasma membrane. Receptor-specific differences in this feedback mechanism may, at least in part, explain the observation that different agonists evoke [Ca(2+) ]c oscillations with different kinetics in the same cell type.
Assuntos
Sinalização do Cálcio , Proteína Quinase C/metabolismo , Receptor de Colecistocinina A/metabolismo , Animais , Células CHO , Simulação por Computador , Cricetinae , Cricetulus , Retroalimentação Fisiológica , Modelos Biológicos , Fosforilação , Processamento de Proteína Pós-TraducionalRESUMO
Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain µ-binding protein 2, mapped on chromosome 11q13, are the cause of the disease. We present the clinical and mutational characteristics of ten patients in the Netherlands who showed considerable clinical variability; they carried six novel mutations, including a deletion of exon 2. However, there were no clear phenotype-genotype correlations.
Assuntos
Debilidade Muscular/genética , Atrofia Muscular Espinal/genética , Mutação/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Atrofias Musculares Espinais da Infância/genética , Pré-Escolar , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Atrofia Muscular Espinal/diagnóstico , Países Baixos , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Atrofias Musculares Espinais da Infância/diagnóstico , Fatores de Transcrição/genéticaRESUMO
Mutations in the X-linked cyclin dependent kinase like 5 (CDKL5) gene have been reported in approximately 80 patients since the first description in 2003. The clinical presentation partly corresponds with Rett syndrome, considering clinical features as intellectual disability, hypotonia, and poor visual, language, and motor development. However, these patients do not meet the consensus criteria for Rett syndrome since they lack the clear period of regression. Furthermore, in contrast to Rett syndrome, patients with CDKL5 mutations, have seizures or infantile spasms starting in the first weeks of life. We present clinical phenotype of 5 girls having a mutation in the CDKL5 gene. All mutations are novel and are pathogenic since they either lead to a frameshift in the reading frame or affect a consensus splice site. Four of the mutations are detected de novo in the affected girl.