Collagen is a major structural protein in the body, providing the framework for tissues such as skin, bone, tendon, cartilage, lung, cornea, and heart valve. Normal collagen biosynthesis requires a stringent regulation of a number of transcriptional, translational, and post-translational events including type-specific synthesis, hydroxylation of prolyl and Iysyl residues, glycosylation of hydroxylysyl residues, disulfide bond formation, secretion, cleavage of extension peptides, fibril formation, and cross-linking. Perturbation in any one step in this sequential process might be expected to result in structurally altered collagen, hence the disease associated with it. Abnormalities in collagen structure or biosynthesis are known to occur in a number of connective tissue diseases such as the Ehlers-Danlos syndrome, osteogenesis imperfecta, the Marfan syndrome, and cutis laxa. We propose to isolate a cDNA for lysyl hydroxylase in order to elucidate the molecular mechanism(s) of the enzyme defect in Type VI Ehlers- Danlos syndrome. We also propose to characterize the mutation causing the synthesis of an abnormal 2(I) collagen chain in a patient with the Marfan syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR017128-23
Application #
2078349
Study Section
Special Emphasis Panel (NSS)
Project Start
1978-09-01
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
23
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Uzawa, Katsuhiro; Yeowell, Heather N; Yamamoto, Kazushi et al. (2003) Lysine hydroxylation of collagen in a fibroblast cell culture system. Biochem Biophys Res Commun 305:484-7
Yeowell, H N; Allen, J D; Walker, L C et al. (2000) Deletion of cysteine 369 in lysyl hydroxylase 1 eliminates enzyme activity and causes Ehlers-Danlos syndrome type VI. Matrix Biol 19:37-46
Yeowell, H N; Walker, L C (1999) Tissue specificity of a new splice form of the human lysyl hydroxylase 2 gene. Matrix Biol 18:179-87
Yeowell, H N; Walker, L C (1999) Prenatal exclusion of Ehlers-Danlos syndrome type VI by mutational analysis. Proc Assoc Am Physicians 111:57-62
Walker, L C; Marini, J C; Grange, D K et al. (1999) A patient with Ehlers-Danlos syndrome type VI is homozygous for a premature termination codon in exon 14 of the lysyl hydroxylase 1 gene. Mol Genet Metab 67:74-82
Yeowell, H N; Walker, L C; Murad, S et al. (1997) A common duplication in the lysyl hydroxylase gene of patients with Ehlers Danlos syndrome type VI results in preferential stimulation of lysyl hydroxylase activity and mRNA by hydralazine. Arch Biochem Biophys 347:126-31
Yeowell, H N; Walker, L C (1997) Ehlers-Danlos syndrome type VI results from a nonsense mutation and a splice site-mediated exon-skipping mutation in the lysyl hydroxylase gene. Proc Assoc Am Physicians 109:383-96
Krol, B J; Murad, S; Walker, L C et al. (1996) The expression of a functional, secreted human lysyl hydroxylase in a baculovirus system. J Invest Dermatol 106:11-6
Yeowell, H N; Walker, L C; Marshall, M K et al. (1995) The mRNA and the activity of lysyl hydroxylase are up-regulated by the administration of ascorbate and hydralazine to human skin fibroblasts from a patient with Ehlers-Danlos syndrome type VI. Arch Biochem Biophys 321:510-6
Yeowell, H N; Marshall, M K; Walker, L C et al. (1994) Regulation of lysyl oxidase mRNA in dermal fibroblasts from normal donors and patients with inherited connective tissue disorders. Arch Biochem Biophys 308:299-305

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