Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.
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.
Van Wesenbeeck
Liesbeth
L
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Odgren
Paul R
PR
Coxon
Fraser P
FP
Frattini
Annalisa
A
Moens
Pierre
P
Perdu
Bram
B
MacKay
Carole A
CA
Van Hul
Els
E
Timmermans
Jean-Pierre
JP
Vanhoenacker
Filip
F
Jacobs
Ruben
R
Peruzzi
Barbara
B
Teti
Anna
A
Helfrich
Miep H
MH
Rogers
Michael J
MJ
Villa
Anna
A
Van Hul
Wim
W
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
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