Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.
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.
Alanay
Yasemin
Y
Pediatric Genetics Unit, Department of Pediatrics, Hacettepe University Medical Faculty, Ankara 06100, Turkey.
Avaygan
Hrispima
H
Camacho
Natalia
N
Utine
G Eda
GE
Boduroglu
Koray
K
Aktas
Dilek
D
Alikasifoglu
Mehmet
M
Tuncbilek
Ergul
E
Orhan
Diclehan
D
Bakar
Filiz Tiker
FT
Zabel
Bernard
B
Superti-Furga
Andrea
A
Bruckner-Tuderman
Leena
L
Curry
Cindy J R
CJ
Pyott
Shawna
S
Byers
Peter H
PH
Eyre
David R
DR
Baldridge
Dustin
D
Lee
Brendan
B
Merrill
Amy E
AE
Davis
Elaine C
EC
Cohn
Daniel H
DH
Akarsu
Nurten
N
Krakow
Deborah
D
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*
D024042:Collagen Type I; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human