A5043449663- Connective tissue disorders research
- Bone and Dental Protein Studies
- Protease and Inhibitor Mechanisms
- Nuclear Structure and Function
- Bone fractures and treatments
- Collagen: Extraction and Characterization
- RNA Research and Splicing
- Signaling Pathways in Disease
- Dermatological and Skeletal Disorders
- Peptidase Inhibition and Analysis
- Bone Metabolism and Diseases
- Bone health and treatments
- Ubiquitin and proteasome pathways
- Macrophage Migration Inhibitory Factor
- Vitamin K Research Studies
- Cancer-related gene regulation
- TGF-β signaling in diseases
- Trace Elements in Health
- Neurological diseases and metabolism
- Dupuytren's Contracture and Treatments
- Cell Adhesion Molecules Research
- RNA modifications and cancer
- Bone health and osteoporosis research
- Metabolism and Genetic Disorders
- Folate and B Vitamins Research
National Institutes of Health
2009-2024
National Human Genome Research Institute
2019-2024
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2011-2020
Matrix Research (United States)
2011-2012
Health and Human Development (2HD) Research Network
2010
Virginia Commonwealth University Medical Center
1998
Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of has long been suspected. Since loss cartilage-associated protein (CRTAP), which required post-translational prolyl 3-hydroxylation collagen, causes severe mice, we investigated whether CRTAP deficiency imperfecta. Three 10 children lethal or who did not have a primary collagen defect yet had excess...
Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens non-collagenous molecules into large cable-like fibrils, yet how fibril interacts cells other binding partners remains poorly understood. To help reveal insights collagen structure-function relationship, a data base was assembled including hundreds ligand sites mutations on two-dimensional model fibril. Visual examination distribution functional sites, statistical analysis mutation...
Osteogenesis imperfecta is a heritable disorder that causes bone fragility. Mutations in type I collagen result autosomal dominant osteogenesis imperfecta, whereas mutations either of two components the prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and 3-hydroxylase 1 [P3H1]) cause recessive with rhizomelia (shortening proximal segments upper lower limbs) delayed folding. We identified siblings who had without rhizomelia. They homozygous start-codon mutation...
Abstract Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2 , which encodes site-2 metalloprotease (S2P). missense mutations two independent kindreds with moderate/severe cause substitutions at highly conserved S2P residues. Mutant has normal stability, but impaired functioning regulated intramembrane proteolysis (RIP) OASIS, ATF6 and SREBP transcription factors, consistent decreased proband secretion...
Cyclophilin B (CyPB), encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that functions independently and as a component of the collagen prolyl 3-hydroxylation complex. CyPB proposed to be major PPIase catalyzing rate-limiting step in folding. Mutations PPIB cause recessively inherited osteogenesis imperfecta type IX, moderately severe lethal bone dysplasia. To investigate role folding post-translational modifications, we generated Ppib−/− mice recapitulate OI...
Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics Ehlers-Danlos syndrome (EDS). We identified 7 children types III or IV OI, plus severe large and small joint laxity early progressive scoliosis. each child OI/EDS, we mutation in the first 90 residues helical region α1(I) collagen. These mutations prevent delay removal procollagen N-propeptide by purified N-proteinase (ADAMTS-2) vitro pericellular...
The 33-kDa matrix protein SPARC (BM-40, osteonectin) binds several collagen types with moderate affinity. collagen-binding site resides in helix alphaA of the extracellular calcium-binding domain and is partially masked by alphaC. Previously, we found that removal alphaC caused a 10-fold increase affinity for collagen, identified amino acids crucial binding site-directed mutagenesis. In this study, used rotary shadowing, CNBr peptides, synthetic peptides to map sites onto collagens I, II,...
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 moderate and lethal forms of recessive OI mutations FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 CyPB, respectively. In one branch, both parents carry deletion PPIB (c.563_566delACAG), causing IX their two children. another child XI has homozygous mutation...
ABSTRACT Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, transmembrane ifitm-like protein most strongly expressed the skeletal system, recessive null mutations SERPINF1, pigment epithelium-derived factor (PEDF). We identified 25-year-old woman with severe OI whose dermal fibroblasts cultured osteoblasts displayed minimal secretion of PEDF, but serum PEDF level was normal range. SERPINF1 sequences were despite bone...
Abstract Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, eight unrelated patients with melorheostosis. The activating (Q56P, K57E K57N) cluster tightly the MEK1 negative regulatory domain. Affected displays pattern increased p-ERK1/2 osteoblast immunohistochemistry. Osteoblasts cultured from affected...
We investigated regions of different helical stability within human type I collagen and discussed their role in intermolecular interactions osteogenesis imperfecta (OI). By differential scanning calorimetry circular dichroism, we measured mapped changes the melting temperature (DeltaTm) for 41 Gly substitutions from 47 OI patients. In contrast to peptides, found no correlations DeltaTm with identity substituting residue. Instead, observed regular variations substitution location triple helix...
The Brtl mouse, a knock-in model for moderately severe osteogenesis imperfecta (OI), has G349C substitution in half of type I collagen alpha1(I) chains. We studied the cellular contribution to bone properties. cortical and trabecular are reduced before after puberty, with BV/TV decreased 40-45%. ObS/BS is comparable wildtype, wildtype marrow generate equivalent number colony-forming units (CFUs) at both ages. However, OcS/BS increased ages (36-45%), as TRACP(+) cell numbers (57-47%). After...
Null mutations in cartilage-associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) cause types VII VIII OI, respectively, two novel recessive forms of osteogenesis imperfecta (OI) with severe to lethal bone dysplasia overmodification the type I collagen helical region. CRTAP P3H1 form a complex cyclophilin B (CyPB) endoplasmic reticulum (ER) which 3-hydroxylates Pro986 residue alpha1(I) alpha1(II) chains. We investigated interaction components fibroblasts from OI patients. Both...
Recessive mutations in FKBP10 at 17q21.2, encoding FKBP65, cause both osteogenesis imperfecta (OI) and Bruck syndrome (OI plus congenital contractures). Contractures are a variable manifestation of null/missense mutations. Kuskokwim (KS) is an autosomal recessive contracture disorder found among Yup'ik Eskimos. Linkage mapping KS to chromosome 17q21, together with contractures as feature mutations, made candidate gene. We identified homozygous three-nucleotide deletion (c.877_879delTAC)...
Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI null mutations TMEM38B was identified. encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms which cause are unknown. We identified 3 probands recessive TMEM38B. TRIC-B protein undetectable proband...
Abstract Hutchinson‐Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. The majority of cases are caused de novo single nucleotide mutation in the LMNA gene that activates cryptic splice donor site, resulting production toxic form lamin A with 50 amino acid internal deletion, termed progerin. We previously reported generation transgenic murine model carrying human...
We demonstrate that 85 N-terminal amino acids of the α1(I) chain participate in a highly stable folding domain, acting as stabilizing anchor for end type I collagen triple helix. This region is bordered by microunfolding region, 15 each chain, which include no proline or hydroxyproline residues and contain chymotrypsin cleavage site. Glycine substitutions acid deletions within N-anchor domain induce its reversible unfolding above 34 °C. The overall helix denaturation temperature reduced 5–6...