Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease.
Kidney Int
; 54(6): 1850-6, 1998 Dec.
Article
em En
| MEDLINE
| ID: mdl-9853249
ABSTRACT
BACKGROUND:
The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and this represents a variant of Dent's disease. Hitherto, 12 mutations of the X-linked renal specific chloride channel, CLCN5, have been reported in the Dent'sJapan variant. To further identify such CLCN5 mutations and to define the structure-function relationships of this channel, we have investigated five unrelated, non-consanguinous Japanese families with this disorder.METHODS:
Leukocyte DNA from probands was used with CLCN5 primers for PCR amplification of the coding region, and the DNA sequences of the products determined. Functional studies were performed by expressing the mutants in Xenopus oocytes.RESULTS:
Five CLCN5 mutations consisting of two nonsense (R648X and R704X), two missense (S270R and L278F) and one acceptor splice site mutation (ag-->cg) in intron 4 were identified. The missense and splice site mutations represent novel abnormalities. Heterologous expression in Xenopus oocytes of wild-type and the missense mutants demonstrated that the mutations, which were translated, either abolished or markedly reduced chloride conductance.CONCLUSIONS:
These results expand the spectrum of CLCN5 mutations associated with this renal disorder and provide insight into possible structure-function relationships. For example, both the missense mutations are located within a short putative loop between two transmembrane domains, and our results suggest that this region may have an important functional role in the regulation of channel activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteinúria
/
Cálculos Renais
/
Cálcio
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Canais de Cloreto
/
Mutação
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Animals
/
Child
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Kidney Int
Ano de publicação:
1998
Tipo de documento:
Article