Two human dwarfing disorders, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), are caused by mutations in cartilage oligomeric matrix protein (COMP). In PSACH chondrocytes, mutations in COMP lead to the formation of abnormally large rough endoplasmic reticulum (RER) with a unique fingerprint appearance. Located within these vesicles are COMP and type IX collagen. These abnormal vesicles are not found in tendon fibroblasts, although these cells secrete COMP. This proposal is aimed at elucidating the molecular mechanism behind the abnormal retention of COMP and type IX collagen in chondrocytes but not in tendon fibroblasts. The following hypotheses were developed from recent studies: Mutant COMP molecules are retained in the RER of chondrocytes because the type III repeats do not fold properly, which leads to the formation of non-native disulfide bonds. These molecules are then interacting with either chondrocyte specific RER molecules and/or with native type IX collagen and/or type IX collagen chains in the process of assembly. This non-native complex cannot be secreted and leads to the accumulation in lamellar structures within the RER of chondrocytes. Secretion of mutant COMP occurs in fibroblasts and dedifferentiated chondrocytes, because these cells do not synthesize type IX collagen or do not contain chondrocyte specific RER proteins.
Specific aims are proposed to determine the structure of normal and mutant thrombospondin type III repeats, to define the disulfide linkages in these repeats and the effects of calcium on structure, and to test binding interactions of mutant COMP with type IX collagen and unfolded type IX collagen chains and with REER proteins of chondrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045582-03
Application #
6375156
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1999-09-30
Project End
2003-02-28
Budget Start
2001-09-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2001
Total Cost
$190,303
Indirect Cost
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239