Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.

Abstract

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.

• Authors: Aileen M Barnes, Wayne A Cabral, MaryAnn Weis, Elena Makareeva, Edward L Mertz, Sergey Leikin, David Eyre, Carlos Trujillo, Joan C Marini
• Journal: Human mutation (Hum Mutat) Vol. 33 Issue 11 Pg. 1589-98 (Nov 2012) ISSN: 1098-1004 [Electronic] United States
• PMID: 22718341 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Published 2012 Wiley Periodicals, Inc.*This article is a US Government work and, as such, is in the public domain of the United States of America.

Chemical References

• Molecular Chaperones
• cyclophilin B
• Collagen
• Cyclophilins
• Tacrolimus Binding Proteins
• FKBP10 protein, human

Topics

• Base Sequence
• Child
• Collagen (chemistry, metabolism)
• Consanguinity
• Cyclophilins (deficiency, genetics)
• DNA Mutational Analysis
• Extracellular Matrix (metabolism)
• Female
• Genes, Recessive
• Humans
• Infant, Newborn
• Male
• Molecular Chaperones (genetics, metabolism)
• Mutation
• Osteogenesis Imperfecta (classification, diagnostic imaging, genetics, metabolism)
• Pakistan
• Pedigree
• Radiography
• Tacrolimus Binding Proteins (deficiency, genetics)