Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans

Liesbeth Van Wesenbeeck, Paul R. Odgren, Fraser Coxon, Annalisa Frattini, Pierre Moens, Bram Perdu, Carole A. MacKay, Els Van Hul, Jean-Pierre Timmermans, Filip Vanhoenacker, Ruben Jacobs, Barbara Peruzzi, Anna Teti, Marie Hermine Helfrich, Michael John Rogers, Anna Villa, Wim Van Hul

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194 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)919-930
Number of pages12
JournalThe Journal of Clinical Investigation
Issue number4
Publication statusPublished - 2 Apr 2007


  • autosomal recessive osteopetrosis
  • pleckstrin homology domains
  • RAB geranylgeranyl transferase
  • ruffled border formation
  • small GTPASE RAB7
  • bone-resorption
  • endocytic pathway
  • IA rat
  • malignant osteopetrosis
  • signal-transduction


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