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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7081
pubmed:dateCreated
2006-3-9
pubmed:abstractText
Mutations in ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, cause osteopetrosis and lysosomal storage disease in humans and mice. Severe osteopetrosis is also observed with mutations in the OSTM1 gene, which encodes a membrane protein of unknown function. Here we show that both ClC-7 and Ostm1 proteins co-localize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Co-immunoprecipitations show that ClC-7 and Ostm1 form a molecular complex and suggest that Ostm1 is a beta-subunit of ClC-7. ClC-7 is required for Ostm1 to reach lysosomes, where the highly glycosylated Ostm1 luminal domain is cleaved. Protein but not RNA levels of ClC-7 are greatly reduced in grey-lethal mice, which lack Ostm1, suggesting that the ClC-7-Ostm1 interaction is important for protein stability. As ClC-7 protein levels in Ostm1-deficient tissues and cells, including osteoclasts, are decreased below 10% of normal levels, Ostm1 mutations probably cause osteopetrosis by impairing the acidification of the osteoclast resorption lacuna, which depends on ClC-7 (ref. 3). The finding that grey-lethal mice, just like ClC-7-deficient mice, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for ClC-7-Ostm1 complexes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1476-4687
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
440
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
220-3
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function.
pubmed:affiliation
Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Falkenried 94, D-20246 Hamburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't