Phenotypes Associated with This Genotype

Genotype
MGI:5896639

• Allelic Composition: Plekhm1^tm1.2Hzhao/Plekhm1^tm1.2Hzhao
• Genetic Background: involves: 129S1/Sv * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

skeleton

abnormal osteoclast morphology ( J:236517 )

• osteoclasts grown on plastic dishes or bovine cortical bone slices exhibit altered morphology with tartrate-resistant acid phosphatase (TRAP) staining clustered in the perinuclear area

• osteoclasts cultured on glass have lysosomes clustered at the perinuclear region as opposed to the cell periphery

• osteoclasts cultured on bone show barely detectable localization of LAMP-2 positive lysosomes at the ruffled border and CTSK (cathepsin K) secretion in the resorption lacuna, while the sealing zone appears intact, indicating defects in lysosome peripheral distribution and ruffled border formation

• in vitro osteoclast differentiation and the cytoskeletal organization of actin and microtubules are relatively normal in osteoclasts cultured on glass and bone

• in vivo, osteoclast number and surface are similar to those in control mice

abnormal osteoclast physiology ( J:236517 )

• in vitro, the bone resorption capacity of osteoclasts cultured on bone slices is markedly decreased, as shown by resorption pit staining and the amount of CTx-I (a bone resorption marker) released in the culture medium

increased trabecular bone volume ( J:236517 )

• at 2 months of age, both sexes exhibit a >60% increase in trabecular bone volume to tissue volume (BV/TV) in long bones and vertebrae

decreased osteoblast cell number ( J:236517 )

• at 2 months of age, osteoblast number and surface are slightly decreased, as shown by histomorphometry analysis of femurs

• however, in vitro differentiation of osteoblasts derived from either calvaria or bone marrow stromal cells is normal

increased bone trabecula number ( J:236517 )

• mice show an increased trabecular number, as measured by micro-CT

decreased bone trabecular spacing ( J:236517 )

• mice show decreased trabecular separation, as measured by micro-CT

increased trabecular bone mass ( J:236517 )

• at 2 months of age, both sexes exhibit a >60% increase in trabecular bone mass in long bones and vertebrae relative to control mice; increased trabecular bone mass persists until 5 months of age

• however, no overt defects are detected in other tissues or organs

decreased bone mineralization ( J:236517 )

• at 2 months of age, femoral bone mineral apposition rate is lower than that in control mice

• however, in vitro bone matrix deposition is normal

decreased bone ossification ( J:236517 )

• at 2 months of age, femoral bone formation rate is lower than that in control mice

decreased bone resorption ( J:236517 )

• in vitro, the bone resorption capacity of osteoclasts cultured on bone slices is markedly decreased, as shown by resorption pit staining and the amount of CTx-I (a bone resorption marker) released in the culture medium

• reduced bone resorption capacity of osteoclasts is caused by defects in the peripheral positioning and secretion of lysosomes rather than defects in cytoskeletal organization

cellular

abnormal lysosome morphology ( J:236517 )

• cultured osteoclasts show defects in lysosome peripheral distribution and ruffled border formation

• mouse embryonic fibroblasts (MEFs) exhibit a slightly increased number of LAMP-2 positive lysosomes around nuclei

decreased lysosomal enzyme secretion ( J:236517 )

• osteoclasts cultured on bone slices show barely detectable secretion of cathepsin K (CTSK, the major lysosomal acidic hydrolase in osteoclasts) in the resorption lacuna beneath the ruffled border

• Ca²⁺-regulated exocytosis of lysosomes is significantly inhibited, as determined by the release of the lysosomal enzyme beta-hexoaminidase in streptolysin-O permeabilized MEFs

hematopoietic system

abnormal osteoclast morphology ( J:236517 )

• osteoclasts grown on plastic dishes or bovine cortical bone slices exhibit altered morphology with tartrate-resistant acid phosphatase (TRAP) staining clustered in the perinuclear area

• osteoclasts cultured on glass have lysosomes clustered at the perinuclear region as opposed to the cell periphery

• osteoclasts cultured on bone show barely detectable localization of LAMP-2 positive lysosomes at the ruffled border and CTSK (cathepsin K) secretion in the resorption lacuna, while the sealing zone appears intact, indicating defects in lysosome peripheral distribution and ruffled border formation

• in vitro osteoclast differentiation and the cytoskeletal organization of actin and microtubules are relatively normal in osteoclasts cultured on glass and bone

• in vivo, osteoclast number and surface are similar to those in control mice

abnormal osteoclast physiology ( J:236517 )

• in vitro, the bone resorption capacity of osteoclasts cultured on bone slices is markedly decreased, as shown by resorption pit staining and the amount of CTx-I (a bone resorption marker) released in the culture medium

immune system

abnormal osteoclast morphology ( J:236517 )

• osteoclasts grown on plastic dishes or bovine cortical bone slices exhibit altered morphology with tartrate-resistant acid phosphatase (TRAP) staining clustered in the perinuclear area

• osteoclasts cultured on glass have lysosomes clustered at the perinuclear region as opposed to the cell periphery

• osteoclasts cultured on bone show barely detectable localization of LAMP-2 positive lysosomes at the ruffled border and CTSK (cathepsin K) secretion in the resorption lacuna, while the sealing zone appears intact, indicating defects in lysosome peripheral distribution and ruffled border formation

• in vitro osteoclast differentiation and the cytoskeletal organization of actin and microtubules are relatively normal in osteoclasts cultured on glass and bone

• in vivo, osteoclast number and surface are similar to those in control mice

abnormal osteoclast physiology ( J:236517 )

• in vitro, the bone resorption capacity of osteoclasts cultured on bone slices is markedly decreased, as shown by resorption pit staining and the amount of CTx-I (a bone resorption marker) released in the culture medium

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive osteopetrosis 6		DOID:0110945	OMIM:611497	J:236517