RESUMEN
GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in the function of the entire proximal tubule. Recent findings reveal the molecular basis of FRTS1: Intramitochondrial fiber aggregation triggered by mutant GATM provides a starting point for proximal tubule damage and drives disease progression. As a rare and newly recognized inherited kidney disease, the complex manifestations of FRTS1 are easily underdiagnosed or misdiagnosed. We discuss the complex phenotype of a 26-year-old woman with onset in infancy and a long history of hypophosphatemic rickets. We also identified a novel heterozygous missense variant in the GATM gene in this patient. The novel variant and phenotype we report expand the disease spectrum of FRTS1. We recommend screening for GATM in children with RFS, especially in patients with resistant rickets who have previously had negative genetic testing. In addition, we found pathological deposition of mutant GATM proteins within mitochondria in the patient's urinary sediment cells by a combination of electron microscopy and immunofluorescence. This unique urine cytology experiment has the potential to be a valuable tool for identifying patients with RRTS1.
Asunto(s)
Síndrome de Fanconi , Fenotipo , Raquitismo Hipofosfatémico , Humanos , Femenino , Adulto , Síndrome de Fanconi/genética , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/patología , Raquitismo Hipofosfatémico/genética , Raquitismo Hipofosfatémico/diagnóstico , Mutación MissenseRESUMEN
Holliday junction recognition protein (HJURP) is involved in the regulation of mortality in various cell types, including renal cell carcinoma (RCC) cells. The specific mechanisms by which HJURP regulates RCC cell apoptosis and the cell cycle have not been previously investigated, to the best of our knowledge. In the present study, the expression of HJURP in RCC tissues and adjacent paracancerous renal tissue, as well as in RCC cell lines, was analyzed using reverse transcriptionquantitative PCR and western blot analysis. The A498 RCC cells were transfected with an HJURP overexpression vector, which resulted in reduced proliferation, as demonstrated using immunofluorescence staining, a Cell Counting Kit8 assay and a colony formation assay. Flow cytometry and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labelling assays were used to determine the effect of HJURP on the cell cycle and apoptosis of RCC cells. Proteins associated with the reactive oxygen species (ROS) status were analyzed using western blot analysis. The expression of HJURP was lower in RCC tissues and cells compared with that in the adjacent paracancerous renal tissues and control cells. Furthermore, overexpression of HJURP resulted in a decrease in cell viability and proliferation in vitro. Overexpression of HJURP resulted in cell cycle arrest at the G0/G1 phase, cell apoptosis and an increase in ROS stress. In addition, the phosphorylated/total sirtuin 1 (SIRT1) protein ratio was decreased, whereas the expression of peroxisome proliferatoractivated receptor (PPAR)γ was increased in the HJURPoverexpressing RCC cells. In clinical practice, decreased HJURP expression may be associated with poor prognosis in patients with RCC. These results suggest that HJURP may regulate cell apoptosis and proliferation in RCC cells and this may be mediated by PPARγ/SIRT1. Thus, HJURP may be used as a predictor of prognosis in patients with RCC.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Proteínas de Unión al ADN/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Especies Reactivas de Oxígeno/metabolismo , Adulto , Anciano , Apoptosis/fisiología , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular , Humanos , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Fase de Descanso del Ciclo Celular , Regulación hacia ArribaRESUMEN
In this paper, a new, fully-automatic method for the quantification of brain atrophy based on CT volume data is put forward by taking advantage of the characteristics of cerebral CT images in combination with the prior medical knowledge. This algorithm has been verified through the calculation of 2388 cases of normal and brain atrophy subjects.