Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10, which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47 and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47 but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency.

Department of Human Genetics

Department of Molecular Cell and Developmental Biology University of California at Los Angeles Los Angeles CA 90095 USA

Department of Orthopaedic Surgery

Department of Orthopaedic Surgery Department of Human Genetics Department of Obstetrics and Gynecology and

Department of Orthopaedic Surgery Department of Molecular Cell and Developmental Biology University of California at Los Angeles Los Angeles CA 90095 USA

Department of Orthopaedics and Sports Medicine University of Washington Seattle WA USA

Department of Pediatrics David Geffen School of Medicine at the University of California at Los Angeles Los Angeles CA 90095 USA Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Murakami T., Saito A., Hino S.I., Kondo S., Kanemoto S., Chihara K., Sekiya H., Tsumagari K., Ochiai K., Yoshinaga K., et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat. Cell Biol. 2009;10:1205–1211. PubMed

Lisse T.S., Thiele F., Fuchs H., Hans W., Przemeck G.K., Abe K., Rathkolb B., Quintanilla-Martinez L., Hoelzlwimmer G., Helfrich M., et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet. 2008;2:e7. PubMed PMC

Forlino A., Cabral W.A., Barnes A.M., Marini J.C. New perspectives on osteogenesis imperfecta. Nat. Rev. Endocrinol. 2011;7:540–557. PubMed PMC

Byers P.H., Pyott S.M. Recessively inherited forms of osteogenesis imperfecta. Annu. Rev. Genet. 2012;46:475–497. PubMed

Marini J.C., Blissett A.R. New genes in bone development: what's new in osteogenesis imperfecta. J. Clin. Endocrinol. Metab. 2013;98:3095–3103. PubMed PMC

Morello R., Bertin T.K., Chen Y., Hicks J., Tonachini L., Monticone M., Castagnola P., Rauch F., Glorieux F.H., Vranka J., et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127:291–304. PubMed

Cabral W.A., Chang W., Barnes A.M., Weis M., Scott M.A., Leikin S., Makareeva E., Kuznetsova N.V., Rosenbaum K.N., Tifft C.J., et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat. Genet. 2007;39:359–365. PubMed PMC

van Dijk F.S., Nesbitt I.M., Zwikstra E.H., Nikkels P.G.J., Piersma S.R., Fratantoni S.A., Jimenez C.R., Huizer M., Morsman A.C., Cobben J.M., et al. PPIB mutations cause severe osteogenesis imperfecta. Am. J. Hum. Genet. 2009;85:521–527. PubMed PMC

Christiansen H.E., Schwarze U., Pyott S.M., AlSwaid A., Balwi A.l.M., Alrasheed S., Pepin M.G., Weis M.A., Eyre D.R., Byers P.H. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am. J. Hum. Genet. 2010;86:389–398. PubMed PMC

Alanay Y., Avaygan H., Camacho N., Utine G.E., Boduroglu K., Aktas D., Alikasifoglu M., Tuncbilek E., Orhan D., Bakar F.T., et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 2010;86:551–559. PubMed PMC

Macdonald J.R., Bächinger H.P. HSP47 binds cooperatively to triple helical type I collagen but has little effect on the thermal stability or rate of refolding. J. Biol. Chem. 2001;276:25399–25403. PubMed

Kojima T., Miyaishi O., Saga S., Ishiguro N., Tsutsui Y., Iwata H. The retention of abnormal type I procollagen and correlated expression of HSP 47 in fibroblasts from a patient with lethal osteogenesis imperfecta. J. Pathol. 1998;184:212–218. PubMed

Drögemüller C., Becker D., Brunner A., Haase B., Kircher P., Seeliger F., Fehr M., Baumann U., Lindblad-Toh K., Leeb T. A missense mutation in the SERPINH1 gene in dachshunds with osteogenesis imperfecta. PLoS Genetics. 2009;5:e1000579. PubMed PMC

Koide T., Takahara Y., Asada S., Nagata K. Xaa-Arg-Gly triplets in the collagen triple helix are dominant binding sites for the molecular chaperone HSP47. J. Biol. Chem. 2002;277:6178–6182. PubMed

Ono T., Miyazaki T., Ishida Y., Uehata M., Nagata K. Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix. J. Biol. Chem. 2012;287:6810–6818. PubMed PMC

Yagi-Utsumi M., Yoshikawa S., Yamaguchi Y., Nishi Y., Kurimoto E., Ishida Y., Homma T., Hoseki J., Nishikawa Y., Koide T., et al. NMR and mutational identification of the collagen-binding site of the chaperone Hsp47. PLoS ONE. 2012;7:e45930. PubMed PMC

Nagai N., Hosokawa M., Itohara S., Adachi E., Matsushita T., Hosokawa N., Nagata K. Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J. Cell Biol. 2000;150:1499–1506. PubMed PMC

Nagata K. HSP47 as a collagen-specific molecular chaperone: function and expression in normal mouse development. Semin. Cell Dev, Biol. 2003;14:275–282. PubMed

Kelley B.P., Malfait F., Bonafé L., Baldridge D., Homan E., Symoens S., Willaert A., Elcioglu N., Van Maldergem L., Verellen-Dumoulin C., et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome. J. Bone Miner. Res. 2011;26:666–672. PubMed PMC

Setijowati E.D., Van Dijk F.S., Cobben J.M., van Rijn R.R., Sistermans E.A., Faradz S.M.H., Kawiyana S., Pals G. A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. Eur. J. Med. Genet. 2012;55:17–21. PubMed

Venturi G., Monti E., Carbonare L.D., Corradi M., Gandini A., Valenti M.T., Boner A., Antoniazzi F. A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect. Bone. 2012;50:343–349. PubMed

Barnes A.M., Cabral W.A., Weis M., Makareeva E., Mertz E.L., Leikin S., Eyre D., Trujillo C., Marini J.C. Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix. Hum. Mutat. 2012;33:1589–1598. PubMed PMC

Shaheen R., Al-Owain M., Sakati N., Alzayed Z.S., Alkuraya F.S. FKBP10 and Bruck syndrome: phenotypic heterogeneity or call for reclassification? Am. J. Hum. Genet. 2010;87:306–307. PubMed PMC

Schwarze U., Cundy T., Pyott S.M., Christiansen H.E., Hegde M.R., Bank R.A., Pals G., Ankala A., Conneely K., Seaver L., et al. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Hum. Mol. Genet. 2012;22:1–17. PubMed PMC

Day A., Dong J., Funari V.A., Harry B., Strom S.P., Cohn D.H., Nelson S.F. Disease gene characterization through large-scale co-expression analysis. PLoS ONE. 2009;4:e8491. PubMed PMC

Söderberg O., Gullberg M., Jarvius M., Ridderstråle K., Leuchowius K-J., Jarvius J., Wester K., Hydbring P., Bahram F., Larsson L.-G., Landegren U. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat. Methods. 2006;3:995–1000. PubMed

Nagata K. Hsp47: a collagen-specific molecular chaperone. Trends. Biochem. Sci. 1996;21:22–26. PubMed

Nagata K., Saga S., Yamada K.M. Characterization of a novel transformation-sensitive heat-shock protein (HSP47) that binds to collagen. Biochem. Biophys. Res. Commun. 1988;153:428–434. PubMed

Masago Y., Hosoya A., Kawasaki K., Kawano S., Nasu A., Toguchida J., Fujita K., Nakamura H., Kondoh G., Nagata K. The molecular chaperone Hsp47 is essential for cartilage and endochondral bone formation. J. Cell Sci. 2012;125:1118–1128. PubMed

Bonadio J., Holbrook K.A., Gelinas R.E., Jacob J., Byers P.H. Altered triple helical structure of type I procollagen in lethal perinatal osteogenesis imperfecta. J. Biol. Chem. 1985;260:1734–1742. PubMed

Bonadio J., Byers P.H. Subtle structural alterations in the chains of type I procollagen produce osteogenesis imperfecta type II. Nature. 1985;316:363–366. PubMed

Weibrecht I., Leuchowius K.-J., Clausson C.-M., Conze T., Jarvius M., Howell W.M., Kamali-Moghaddam M., Söderberg O. Proximity ligation assays: a recent addition to the proteomics toolbox. Expert Rev Proteomics. 2010;7:401–409. PubMed

Endoplasmic reticulum stress disrupts signaling via altered processing of transmembrane receptors

4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta

A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen