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1.
Nat Genet ; 37(7): 739-44, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15924139

RESUMO

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.


Assuntos
Canais de Cálcio/metabolismo , Glomerulosclerose Segmentar e Focal/genética , Glomérulos Renais/metabolismo , Adolescente , Adulto , Canais de Cálcio/genética , Canais de Cálcio/fisiologia , Células Cultivadas , Cromossomos Humanos Par 11/genética , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Glomérulos Renais/patologia , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Mutação , Linhagem , Canais de Cátion TRPC , Canal de Cátion TRPC6
2.
Environ Monit Assess ; 171(1-4): 129-47, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20556652

RESUMO

At the Bear Brook Watershed in Maine (BBWM), the forest tree composition was characterized and the effects of the chronic ammonium sulfate ((NH(4))(2)SO(4)) treatment on basal area growth, foliar chemistry, and gas exchange were investigated on forest species. The BBWM is a paired watershed forest ecosystem study with one watershed, West Bear (WB), treated since 1989 with 26.6 kg N ha(-1) year(-1) and 30 kg S ha(-1) year(-1)applied bimonthly as (NH(4))(2)SO(4), while the other watershed, East Bear (EB), serves as a reference. Tree species richness, density, and mortality were found to be similar between watersheds. Basal area increment was estimated from red spruce and sugar maple, showing that, for the first 7 years of treatment, it was significantly higher for sugar maple growing in WB compared to EB, but no differences were observed for red spruce between watersheds. However, the initial higher sugar maple basal area growth in WB subsequently decreased after 8 years of treatment. Foliar chemical analysis performed in trees, saplings, and ground flora showed higher N concentrations in the treated WB compared to the reference EB. But, foliar cation concentrations, especially Ca and Mg, were significantly lower for most of the species growing in WB compared with those growing in EB. For sugar maple, foliar N was higher on WB, but there were no differences in foliar Ca and Mg concentrations between treated and reference watersheds. In addition, only sugar maple trees in the treated WB showed significantly higher photosynthetic rates compared to reference EB trees.


Assuntos
Sulfato de Amônio/farmacologia , Árvores/efeitos dos fármacos , Ecossistema , Monitoramento Ambiental , Humanos , Maine , Nitrogênio/metabolismo , Folhas de Planta/química , Solo/análise , Enxofre/metabolismo , Árvores/química , Água
3.
J Am Soc Nephrol ; 16(12): 3694-701, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16251236

RESUMO

Mutations in the alpha-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.


Assuntos
Actinina/genética , Predisposição Genética para Doença/epidemiologia , Glomerulosclerose Segmentar e Focal/genética , Proteínas dos Microfilamentos/genética , Mutação Puntual/genética , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Genótipo , Glomerulosclerose Segmentar e Focal/epidemiologia , Humanos , Incidência , Masculino , Mutagênese , Linhagem , Reação em Cadeia da Polimerase/métodos , Probabilidade , Sensibilidade e Especificidade , Análise de Sequência de DNA
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