TY - JOUR
T1 - Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta
AU - Alanay, Yasemin
AU - Avaygan, Hrispima
AU - Camacho, Natalia
AU - Utine, G. Eda
AU - Boduroglu, Koray
AU - Aktas, Dilek
AU - Alikasifoglu, Mehmet
AU - Tuncbilek, Ergul
AU - Orhan, Diclehan
AU - Bakar, Filiz Tiker
AU - Zabel, Bernard
AU - Superti-Furga, Andrea
AU - Bruckner-Tuderman, Leena
AU - Curry, Cindy J.R.
AU - Pyott, Shawna
AU - Byers, Peter H.
AU - Eyre, David R.
AU - Baldridge, Dustin
AU - Lee, Brendan
AU - Merrill, Amy E.
AU - Davis, Elaine C.
AU - Cohn, Daniel H.
AU - Akarsu, Nurten
AU - Krakow, Deborah
N1 - Funding Information:
Y.A. was supported by TUBITAK (2219 Program). D.K., D.H.C., D.R.E., and B.L. were supported by NIHCD HD22657. D.K. and D.H.C. were also supported by NIH R01DE019567. B.Z. and A.S.F. are supported by SKELNET and EuroGrow. E.C.D. is a Canada Research Chair. We also acknowledge the support of the Facility for Electron Microscopy Research (FEMR) at McGill University.
PY - 2010/4/9
Y1 - 2010/4/9
N2 - 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 α1(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.
AB - 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 α1(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.
UR - http://www.scopus.com/inward/record.url?scp=77950381244&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2010.02.022
DO - 10.1016/j.ajhg.2010.02.022
M3 - Article
C2 - 20362275
AN - SCOPUS:77950381244
VL - 86
SP - 551
EP - 559
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -