Assuntos
Benzotiazóis/uso terapêutico , Genótipo , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Benzotiazóis/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Compostos de Fenilureia/farmacologia , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Jagged1 (JAG1) is a cell surface ligand in the Notch signaling pathway and mutations in this gene cause Alagille syndrome (AGS). JAG1 mutations have been identified in 60-70% of AGS patients studied, and these include total gene deletions ( approximately 6%), protein-truncating mutations (insertions, deletions and nonsense mutations) (82%) and missense mutations (12%). Based on the finding that total JAG1 deletions cause AGS, haploinsufficiency has been hypothesized to be a mechanism for disease causation; however, the mechanism by which missense mutations cause disease is not understood. To date, 25 unique missense mutations have been observed in AGS patients. Missense mutations are non-randomly distributed across the protein with clusters at the 5' end of the protein, in the conserved DSL domain, and two clusters within the EGF repeats. To understand the effect of the missense mutations on protein localization and function, we have studied four missense mutations (R184H, L37S, P163L and P871R). In two assays of JAG1 function, R184H and L37S are associated with loss of Notch signaling activity relative to wild-type JAG1. Neither R184H or L37S is present on the cell surface and both are abnormally glycosylated. Furthermore, these mutations lead to abnormal accumulation of the protein, possibly in the endoplasmic reticulum. Both P163L and P871R are associated with normal levels of Notch signaling activity and are present on the cell surface, consistent with these changes being polymorphisms rather than disease-causing mutations.
Assuntos
Síndrome de Alagille/genética , Líquido Intracelular/metabolismo , Mutação de Sentido Incorreto , Processamento de Proteína Pós-Traducional/genética , Proteínas/genética , Proteínas/metabolismo , Células 3T3 , Substituição de Aminoácidos/genética , Animais , Arginina/genética , Transporte Biológico Ativo/genética , Proteínas de Ligação ao Cálcio , Linhagem Celular , Glicosilação , Histidina/genética , Peptídeos e Proteínas de Sinalização Intercelular , Proteína Jagged-1 , Leucina/genética , Proteínas de Membrana/genética , Camundongos , Receptores Notch , Serina/genética , Proteínas Serrate-Jagged , Transdução de Sinais/genéticaRESUMO
We present a patient with bilateral retinoblastoma and developmental delay who has an abnormal male karyotype containing 47 chromosomes, including an acentric derivative chromosome 13. We postulate that the derivative 13 occurred after a break at 13q14, with the proximal portion of the chromosome forming a ring and the distal portion undergoing duplication. Thus, this patient is trisomic for 13q14-->qter. The derivative chromosome with duplicated distal portion (13q14-->qter) lacked the 13 centromere and was negative for chromosome 13 alpha-satellite DNA by low stringency FISH. Nevertheless, this chromosome is stably transmitted in lymphocytes and fibroblasts. A single primary constriction was observed at band 13q21, consistent with activation of a latent centromere (neocentromere) at this band. The neocentromere on der(13) was positive for multiple centromeric proteins, suggesting that it acts as the functional centromere. By FISH, the Rb gene was present on the normal 13, the proximally derived ring chromosome, but not on the derivative chromosome. Although there was no evidence for disruption of the Rb gene, this chromosome rearrangement most likely results in abnormal expression of the Rb gene product.
Assuntos
Centrômero/genética , Cromossomos Humanos Par 13/genética , Neoplasias da Retina/genética , Retinoblastoma/genética , Cromossomos em Anel , Bandeamento Cromossômico , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Proteína do Retinoblastoma/genéticaRESUMO
Rothmund-Thomson syndrome is an autosomal recessive disorder characterized by poikilodermatous skin changes that develop in infancy. Associated manifestations include juvenile cataracts, sparse hair, short stature, skeletal defects, dystrophic nails and teeth, and hypogonadism. An increased incidence of malignancy, including osteosarcoma, has been reported in patients with Rothmund-Thomson syndrome. The molecular basis of the disorder is not known. This report describes a patient with Rothmund-Thomson syndrome in whom two primary osteosarcomas developed 12 years apart. The presentation, diagnosis, and treatment of osteosarcoma in this patient with Rothmund-Thomson syndrome are described. Cytogenetic and molecular analysis of peripheral blood and skin fibroblasts had low level mosaicism for trisomy of chromosomes 2 and 8. Although several patients have been described with mosaic trisomy 8 and i(2q) (mosaic isochromosome for the long arm of chromosome 2), the patient described here is the first to have mosaic trisomy for the entire chromosomes 2 and 8. The cytogenetic findings in this patient are consistent with an underlying defect in chromosomal stability.
