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Heterogeneity in the processing of CLCN5 mutants related to Dent disease. | LitMetric

Heterogeneity in the processing of CLCN5 mutants related to Dent disease.

Hum Mutat

UPMC Univ Paris 06, UMR_S 872, Laboratoire de Génomique, Physiologie et Physiopathologie Rénales, Paris, France.

Published: April 2011

AI Article Synopsis

  • - The study focuses on nine known pathogenic mutations in the ClC-5 gene, linked to Dent disease, an X-linked disorder affecting kidney function.
  • - Researchers analyzed the behavior of these mutations in both frog oocytes and human cell lines, finding that some mutants reach the cell surface but have reduced functionality, while others are improperly processed and nonfunctional.
  • - The findings highlight different cellular mechanisms that lead to ClC-5 dysfunction, revealing that mutations can impact protein processing and stability, ultimately resulting in diminished or absent currents.

Article Abstract

Mutations in the electrogenic Cl(-)/H(+) exchanger ClC-5 gene CLCN5 are frequently associated with Dent disease, an X-linked recessive disorder affecting the proximal tubules. Here, we investigate the consequences in Xenopus laevis oocytes and in HEK293 cells of nine previously reported, pathogenic, missense mutations of ClC-5, most of them which are located in regions forming the subunit interface. Two mutants trafficked normally to the cell surface and to early endosomes, and displayed complex glycosylation at the cell surface like wild-type ClC-5, but exhibited reduced currents. Three mutants displayed improper N-glycosylation, and were nonfunctional due to being retained and degraded at the endoplasmic reticulum. Functional characterization of four mutants allowed us to identify a novel mechanism leading to ClC-5 dysfunction in Dent disease. We report that these mutant proteins were delayed in their processing, and that the stability of their complex glycosylated form was reduced, causing lower cell surface expression. The early endosome distribution of these mutants was normal. Half of these mutants displayed reduced currents, whereas the other half showed abolished currents. Our study revealed distinct cellular mechanisms accounting for ClC-5 loss of function in Dent disease.

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Source
http://dx.doi.org/10.1002/humu.21467DOI Listing

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