title: Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.
abstract: Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24(-/-)) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24(-/-) mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice. Zmpste24(-/-) mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24(-/-) mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141-9100, USA. mbergo@gladstone.ucsf.edu
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.forename: Bryant
authors.initials: B
authors.lastname: Gavino
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schmidt
authors.forename: Christine
authors.initials: C
authors.lastname: Hong
authors.forename: Lonnie V
authors.initials: LV
authors.lastname: Kendall
authors.forename: Andreas
authors.initials: A
authors.lastname: Mohr
authors.forename: Margarita
authors.initials: M
authors.lastname: Meta
authors.forename: Harry
authors.initials: H
authors.lastname: Genant
authors.forename: Yebin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Erik R
authors.initials: ER
authors.lastname: Wisner
authors.forename: Nicholas
authors.initials: N
authors.lastname: Van Bruggen
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Susan
authors.initials: S
authors.lastname: Michaelis
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Griffey
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000367:Age Factors; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000293:injuries*; D002462:Cell Membrane / Q000201:enzymology*; D005347:Fibroblasts / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D008666:Metalloendopeptidases / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018908:Muscle Weakness / Q000235:genetics; D009132:Muscles / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D001426:Bacterial Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C443480:icmT protein, Legionella pneumophila; C440308:lamin C; C090764:prelamin A; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse