title: Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Van Wesenbeeck
authors.forename: Paul R
authors.initials: PR
authors.lastname: Odgren
authors.forename: Fraser P
authors.initials: FP
authors.lastname: Coxon
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
authors.forename: Pierre
authors.initials: P
authors.lastname: Moens
authors.forename: Bram
authors.initials: B
authors.lastname: Perdu
authors.forename: Carole A
authors.initials: CA
authors.lastname: MacKay
authors.forename: Els
authors.initials: E
authors.lastname: Van Hul
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Filip
authors.initials: F
authors.lastname: Vanhoenacker
authors.forename: Ruben
authors.initials: R
authors.lastname: Jacobs
authors.forename: Barbara
authors.initials: B
authors.lastname: Peruzzi
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D000071183:Autophagy-Related Proteins; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000502:physiology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000502:physiology; D009154:Mutation; D009928:Organ Specificity; D010022:Osteopetrosis / Q000235:genetics*; D010375:Pedigree; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D008562:Membrane Glycoproteins; C476215:PLEKHM1 protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716466:rab7 GTP-binding proteins, rat; D020691:rab GTP-Binding Proteins