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

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