Department of Cell Biology
Medical Subject Headings
Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Chromosome Mapping; *Chromosomes, Human, Pair 10; Female; Gene Expression Regulation; Humans; Kidney; Male; Membrane Glycoproteins; Monocytes; Mutation; Organ Specificity; Osteopetrosis; Pedigree; Rats; rab GTP-Binding Proteins
This study illustrates that Plekhm1 is an essential protein for bone resorption, as loss-of-function mutations were found to underlie the osteopetrotic phenotype of the incisors absent rat as well as an intermediate type of human osteopetrosis. Electron and confocal microscopic analysis demonstrated that monocytes from a patient homozygous for the mutation differentiated into osteoclasts normally, but when cultured on dentine discs, the osteoclasts failed to form ruffled borders and showed little evidence of bone resorption. The presence of both RUN and pleckstrin homology domains suggests that Plekhm1 may be linked to small GTPase signaling. We found that Plekhm1 colocalized with Rab7 to late endosomal/lysosomal vesicles in HEK293 and osteoclast-like cells, an effect that was dependent on the prenylation of Rab7. In conclusion, we believe PLEKHM1 to be a novel gene implicated in the development of osteopetrosis, with a putative critical function in vesicular transport in the osteoclast.
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Citation: J Clin Invest. 2007 Apr;117(4):919-30. Link to article on publisher's site