RESUMEN
Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.
Asunto(s)
Actinina/fisiología , Cromosomas Humanos Par 19/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Proteínas de Microfilamentos , Actinina/deficiencia , Actinina/genética , Actinas/metabolismo , Secuencia de Aminoácidos , Citoesqueleto/metabolismo , Citoesqueleto/ultraestructura , Análisis Mutacional de ADN , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Predisposición Genética a la Enfermedad , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/genética , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
Seventy-three members of a 100-member kindred with asymptomatic proteinuria, nephrotic syndrome, and progressive renal failure were studied. Of those studied, 11 members had progressed to end-stage renal disease and seven had significant proteinuria (greater than 1 g/24 hours) with normal renal function. The genetic mode of inheritance was autosomal dominant with variable penetrance and expressivity. Histopathologic changes were variable but included focal segmental glomerulosclerosis and diffuse glomerulosclerosis. Renal failure usually occurred in the fifth decade of life. The most consistent clinical finding was proteinuria without microscopic hematuria or other significant urinary sediment elements. This disease differed from Alport's hereditary nephritis and congenital nephrotic syndrome in age of onset, urinary findings, and associated conditions, that is, nerve deafness. The hereditary proteinuria and nephrotic syndrome described in this kindred represents another facet in the spectrum of hereditary renal disease.
Asunto(s)
Glomerulonefritis/genética , Síndrome Nefrótico/genética , Proteinuria/genética , Adolescente , Adulto , Anciano , Biopsia , Femenino , Glomerulonefritis/patología , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/patología , Linaje , Proteinuria/patología , SíndromeRESUMEN
The search for microorganisms that are capable of catalyzing the reduction of an electrode within a fuel cell has primarily been focused on bacteria that operate mesobiotically. Bacteria that function optimally under extreme conditions are beginning to be examined because they may serve as more effective catalysts (higher activity, greater stability, longer life, capable of utilizing a broader range of fuels) in microbial fuel cells. An examination of marine sediment from temperate waters (Charleston, SC) proved to be a good source of thermophilic electrode-reducing bacteria. Electric current normalized to the surface area of graphite electrodes was approximately ten times greater when sediment fuel cells were incubated at 60 degrees C (209 to 254 mA/m(2)) vs 22 degrees C (10 to 22 mA/m(2)). Electricity-generating communities were selected in sediment fuel cells and then maintained without sediment or synthetic electron-carrying mediators in single-chambered fuel cells. Current was generated when cellulose or acetate was added as a substrate to the cells. The 16S ribosomal ribonucleic acid genes from the heavy biofilms that formed on the graphite anodes of acetate-fed fuel cells were cloned and sequenced. The preponderance of the clones (54 of 80) was most related to a Gram-positive thermophile, Thermincola carboxydophila (99% similarity). The remainder of clones from the community was most related to T. carboxydophila, or uncultured Firmicutes and Deferribacteres. Overall, the data indicate that temperate aquatic sediments are a good source of thermophilic electrode-reducing bacteria.
Asunto(s)
Electricidad , Sedimentos Geológicos/microbiología , Bacterias Grampositivas/aislamiento & purificación , Bacterias Grampositivas/metabolismo , Acetatos/metabolismo , Biopelículas/crecimiento & desarrollo , Celulosa/metabolismo , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Electrodos , Bacterias Grampositivas/clasificación , Bacterias Grampositivas/genética , Grafito/metabolismo , Calor , Datos de Secuencia Molecular , Oxidación-Reducción , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , South CarolinaRESUMEN
We performed a genome-wide linkage analysis search for a genetic locus responsible for kidney dysfunction in a large family. This inherited condition, characterized by proteinuria, progressive renal insufficiency, and focal segmental glomerulosclerosis, follows autosomal dominant inheritance. We show with a high degree of certainty (maximum 2-point lod score 12.28) that the gene responsible for this condition is located on chromosome 19q13.