title: Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.
abstract: Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.
authors.affiliation: Pediatric Genetics Unit, Department of Pediatrics, Hacettepe University Medical Faculty, Ankara 06100, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Hrispima
authors.initials: H
authors.lastname: Avaygan
authors.forename: Natalia
authors.initials: N
authors.lastname: Camacho
authors.forename: G Eda
authors.initials: GE
authors.lastname: Utine
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.forename: Dilek
authors.initials: D
authors.lastname: Aktas
authors.forename: Mehmet
authors.initials: M
authors.lastname: Alikasifoglu
authors.forename: Ergul
authors.initials: E
authors.lastname: Tuncbilek
authors.forename: Diclehan
authors.initials: D
authors.lastname: Orhan
authors.forename: Filiz Tiker
authors.initials: FT
authors.lastname: Bakar
authors.forename: Bernard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Cindy J R
authors.initials: CJ
authors.lastname: Curry
authors.forename: Shawna
authors.initials: S
authors.lastname: Pyott
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.forename: Dustin
authors.initials: D
authors.lastname: Baldridge
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: Amy E
authors.initials: AE
authors.lastname: Merrill
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Nurten
authors.initials: N
authors.lastname: Akarsu
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D024042:Collagen Type I / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human