This project is defining at the protein level the molecular basis of heritable disorders of collagen metabolism that cause skeletal disease. The goal is to understand the consequences of mutations in collagen genes in terms of expressed protein structure and altered macromolecular interactions in the extracellular matrix.
The specific aims i nclude understanding the molecular effects of type II collagen defects that include amino acid substitutions caused by single base changes and full and partial exon deletions caused by splice site mutations. Rules in the relationship between underlying gene defect, expressed protein abnormality, tissue pathology and clinical phenotype will be explored. Changes in post-translational chemistry of collagen molecules bearing mutant chains, that is in proline hydroxylation, lysine hydroxylation, hydroxylysine glycosylation and intermolecular cross-linking will be examined, pursuing an hypothesis that the quality of such secondary changes are important determinants of the clinical phenotype and disease severity. The approach is to apply methods in protein analysis (peptide mapping and gas-phase sequencing adapted for the special features of collagen chemistry) to human tissue specimens. Tissues from defined cases of chondrodysplasia including achondrogenesis/hypochondrogenesis, spondyloepiphyseal dysplasia (SED), spondyloepimetaphyseal dysplasia (SEMD), Kniest dysplasia and familial osteoarthrosis/mild SED will be studied. Defects at the protein level in collagen types IX, X and XI will also be sought in the extracellular matrix using a similar approach. The nature of the collagen cross-linking defect in Ehlers-Danlos syndrome VI will be pursued. Common features of the pathology of bone matrix collagen in osteogenesis imperfecta will also be explored at the protein level. The significance of the work is the major impact collectively of overt heritable skeletal diseases, and also of related mild mutations and genetic polymorphisms that are strongly suspected to predispose to the common disorders of the aging skeleton, osteoporosis and osteoarthritis. With the increasing burden in life quality and health care delivery of degenerative disorders of the skeleton, understanding the molecular basis and prevalence of such genetic factors is essential if effective diagnostic, preventive and therapeutic strategies are to be pursued.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR037318-13
Application #
2856135
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Tyree, Bernadette
Project Start
1986-07-01
Project End
2000-07-31
Budget Start
1999-01-01
Budget End
2000-07-31
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Orthopedics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hudson, David M; Archer, Marilyn; King, Karen B et al. (2018) Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J Biol Chem 293:15620-15627
Cundy, Tim; Dray, Michael; Delahunt, John et al. (2018) Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype. J Bone Miner Res 33:1260-1271
Gistelinck, Charlotte; Kwon, Ronald Y; Malfait, Fransiska et al. (2018) Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies. Proc Natl Acad Sci U S A 115:E8037-E8046
Hudson, David M; Weis, MaryAnn; Rai, Jyoti et al. (2017) P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA. J Biol Chem 292:3877-3887
Hudson, D M; Garibov, M; Dixon, D R et al. (2017) Distinct post-translational features of type I collagen are conserved in mouse and human periodontal ligament. J Periodontal Res 52:1042-1049
Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo et al. (2017) Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res 32:1354-1367
Heard, Melissa E; Besio, Roberta; Weis, MaryAnn et al. (2016) Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation. PLoS Genet 12:e1006002
Fratzl-Zelman, Nadja; Barnes, Aileen M; Weis, MaryAnn et al. (2016) Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization. J Clin Endocrinol Metab 101:3516-25
Gistelinck, Charlotte; Witten, Paul Eckhard; Huysseune, Ann et al. (2016) Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome. J Bone Miner Res 31:1930-1942
Cabral, Wayne A; Ishikawa, Masaki; Garten, Matthias et al. (2016) Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. PLoS Genet 12:e1006156

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