Underlying structural defects of collagen are being sought in human connective tissues diseases. Of particular interest are those inborn disorders that affect the musculoskeleton, the more common ones being the Ehlers-Danlos syndromes, osteogenesis imperfecta, and Marfan's syndrome. A rich source of such rare tissues is available to us here and through collaborative contacts. Our primary approach is direct analysis of tissue matrix collagens by biochemical techniques. A portion of effort is spent screening promising new cases, but the main effort is devoted to follow-up studies in depth on identified collagen mutants. Though collagen disorders are the prime target, signs of proteoglycan defects would be pursued. A major goal is to gain unique insights on the relationship between structure and function of collagen, as well as helping detect, treat and prevent these skeletal disorders. Collagen cross-linking receives keen attention since cross-linking defects are common to many of the known diseases of the collagen molecule, and seems a good index of structural integrity. Techniques include slabgel electrophoresis and reverse phase HPLC chromatography of collagen polypeptides and derived fragments, and electronmicroscopy of collagen fibrils and cells in affected tissues. Where appropriate skin fibroblasts will be grown to characterize procollagen products. Appropriate tissue specimens will be frozen for future DNA and RNA analyses by collaborators should defects be indicated at the protein level. Specific cases for follow-up identified in the last two years by tissue screening include: 1) a new case of EDS VII in which a short deletion spanning the Alpha2(I)-chain amino-telopeptide domain is indicated; 2) a new case of EDS VI with no hydroxylysine in skin and lysyl pyridinoline replacing hydroxylysyl pyridinoline cross-links in cartilage; 3) two lethal newborn cases of spondylepiphyseal dysplasia in which a structural mutation of Alpha1(II) is present; 4) achondrogenesis type II (Langer-Saldino) that totally lacks type II collagen in cartilage; and 5) bone from several cases of osteogenesis imperfecta. In addition we will screen for cross-linking abnormalities in aortic collagen of Marfan's patients. Inborn disorders that impair the structure and development of the skeleton account for a significant fraction of the 12 million Americans who have birth defects. Collagen abnormalities will account for a significant number of these.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 109 publications