Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.
Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% over-modification. Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix.
Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Aileen M
AM
Barnes
Wayne A
WA
Cabral
MaryAnn
M
Weis
Elena
E
Makareeva
Edward L
EL
Mertz
Sergey
S
Leikin
David
D
Eyre
Carlos
C
Trujillo
Joan C
JC
Marini
D001483:Base Sequence; D002648:Child; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D003241:Consanguinity; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics; D004252:DNA Mutational Analysis; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000145:classification / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism*; D010154:Pakistan; D010375:Pedigree; D011859:Radiography; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics*
D018832:Molecular Chaperones; C081786:cyclophilin B; D003094:Collagen; D021983:Cyclophilins; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human