Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-10-03
2001-07-24
Horlick, Kenneth R. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06265157
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is detecting altered collagen gene sequences.
BACKGROUND OF THE INVENTION
The collagen genes are an important family of genes, the products of which provide the extracellular framework for virtually all multicellular organisms (Bornstein et al., 1980 Ann. Rev. Biochem. 49:957-1003). More than nineteen distinct types of collagen have been described (Ramirez et al., 1985, Ann. New York Acad. Sci. 460:117-129; Vuorio et al., 1990, Annu. Rev. Biochem. 59:837-872; Chu et al., 1993, In:
Connective Tissue and Its Heritable Disorders
, Royce et al., eds., Wiley-Liss, New York, pp.149-165; Prockop et al., 1995, Annu. Rev. Biochem. 64:403-434). The biosynthesis of collagen has been described (Prockop et al., 1979, N. Eng. J. Med. 301:13-23).
Large collagen structures form by nucleated growth of collagen chains into triple helical collagen subunits. Collagen fibrils form by nucleated growth of collagen subunits, a fibril comprising a quarter-staggered array of subunits (Gross et al., 1958, Annu. Rev. Cell Biol. 2:421-457; Wood et al., 1960, Biochem. J. 75:588:598; Prockop et al., 1984, N. Eng. J. Med. 311:376-386; Kadler et al., 1987, J. Biol. Chem. 262:15696-15701; Na et al., 1989, Biochem. 28: 7153-7161; Kadler et al., 1990, Biochem. J. 268:339-343; Prockop et al., 1989, Biophysics (Eng. Transl. Biofizika) 3:81-89). During nucleated growth, the collagen protein chains fold into the triple helical conformation that is a unique and characteristic feature of all collagens (Engel, 1987, Adv. Meat. Res. 4:145-158; Engel et al., 1991, Annu. Rev. Biophys. Biophys. Chem. 20:137-152; Piez, 1984, In:
Extracellular Matrix Biochemistry
, Piez et al., eds., Elsevier Science Pub. Co. Inc., New York, pp. 1-40).
Each of the three &agr;chains in a collagen subunit comprises a repeating tripeptide sequence having the general amino acid sequence Gly-X-Y. The presence of glycine, the smallest amino acid, in every third position is critical, since the amino acid in this position fits into a restricted space in which the three chains come together in the center of the triple helix. The X-and Y-amino acid residues are frequently proline and 4-hydroxyproline, respectively. Because the highly flexible glycine bonds flank the relatively inflexible peptide bonds of proline and 4-hydroxyproline (Hyp), individual &agr; chains do not independently fold into any defined three-dimensional structure. Instead, the chains fold into a defined structure only by forming hydrogen bonds and water bridges that link the Gly-X-Y sequences in one &agr; chain to equivalent Gly-X-Y sequences in the two other &agr; chains.
It is essential to proper collagen molecule conformation that the three a chains are in register, in the sense that the Gly-X-Y tripeptide units in one chain are hydrogen-bonded to the corresponding tripeptide units in the other two &agr; chains. Otherwise, the chains have exposed ends or internal loops of non-triple-helical tripeptide units. Substitution of one or more amino acids of the Gly-X-Y tripeptide sequence with other amino acids, particularly substitution of Gly with an amino acid having a relatively bulky side chain, can produce a structurally abnormal but partially functional collagen subunit. A large number of mutations comprising said substitutions have been described (e.g. Kuivaniemi et al., 1991, FASEB J. 5:2052-2060). Numerous diseases and disorders are associated with mutations in one or more of the Type I or Type IX collagen genes including, but not limited to, osteoporosis, osteoarthritis, chondrodysplasia, multiple epiphyseal dysplasia, osteogenesis imperfecta, shortness of stature, scoliosis, low bone density, and degenerative joint disease.
Type 1 Collagen
Type I collagen accounts for about 80 to 90% of the protein found in bone. It is also found in large amounts in tissues such as skin, ligaments, and tendons. In many tissues, the Type I collagen fibrils are associated with other types of collagen and with other components of the extracellular matrix.
Type I collagen is synthesized as a precursor denoted Type I procollagen, which comprises two pro&agr;1(I) chains and one pro&agr;2(I) chain. Each pro&agr; chain comprises three separate domains, namely an N-propeptide domain, a central domain, and a C-propeptide domain.
The N-propeptide domain located at the amino-terminal end of each pro&agr; chain comprises a globular subdomain, a short triple-helical subdomain, and another short subdomain that forms part of the cleavage site at which the N-propeptide is separated from the mature collagen molecule.
The central domain of each pro&agr; chain is denoted the &agr;-chain domain, which comprises about several hundred amino acid residues and, with the exception of a short sequence at the end of the domain, every third amino acid is glycine. The &agr;-chain largely comprises the Gly-X-Y tripeptide repeating unit.
The globular C-propeptide domain located at the carboxyl-terminal end of each pro&agr; chain is responsible for association of the pro&agr; chains during biosynthesis of collagen. Hydrophobic and electrostatic interactions among the C-propeptide domains of the three pro&agr; chains direct inclusion of two pro&agr;1(I) chains and one pro&agr;2(I) chain into the procollagen molecule. Formation of interchain disulfide bonds among the pro&agr; subunits further stabilizes the structure of the procollagen molecule, provides the correct registration of the Gly-X-Y tripeptide units of the three chains, and forms a triple helical nucleus of Gly-X-Y units of the three chains. After formation of the triple helical nucleus, triple helical association of the Gly-X-Y units of the three chains proceeds in a zipper-like fashion from the carboxyl-toward the amino-terminal portions of the three chains.
Biosynthesis of the procollagen molecule involves a large number of post-translational modifications, requiring at least eight procollagen-specific enzymes and several non-specific enzymes. Over a hundred amino acids in each a chain are modified post-translationally. After procollagen is assembled, it is secreted from cells. Extracellularly, the N-propeptide is cleaved from the procollagen molecule by one enzyme and the C-propeptide is cleaved from the procollagen molecule by a second enzyme, yielding an individual mature collagen subunit. The solubility of the collagen subunit is about two thousand times lower than the solubility of the corresponding procollagen subunit. Low collagen solubility drives spontaneous polymerization of collagen subunits into collagen fibrils. Indeed, in vitro assembly of collagen subunits formed by enzymatic cleavage of procollagen subunits has been demonstrated (Prockop et al., 1989, In:
Cytoskeletal and Extracellular Proteins
, Aebi et al., eds., Springer Series in Biophysics, Vol. 3, pp. 81-89; Kadler et al., 1990, Biochem J. 268:339-343).
Human pro&agr;1(I) is encoded by the COL1A1 gene, which is located on chromosome 17q21.3-q22, and human pro&agr;2(I) is encoded by the COL1A2 gene, which is located on chromosome 7q21.3-q22. Oligonucleotide primers useful for amplifying and sequencing cDNA encoding the human pro&agr;1(I) chain of Type I procollagen have been described (Labhard et al., 1990, Matrix 10: 124-130).
The complete cDNA sequence corresponding to the COL1A1 gene has been reported (Chu et al., 1984, Nature 310:337-340; Tromp et al., 1988, Biochem. J. 253:919-922; Bernard et al., 1983, Biochem. 22:5213-5223). Furthermore, the nucleotide sequence of approximately 400 base pairs of the 5′-untranslated region, introns 1-26, and twenty-six nucleotides at the 5′-end of intron 27 of COL1A2 have been reported (Chu et al., 1985, J. Biol. Chem. 260:2315-2320; D'Alessio et al., 1988, Gene 67:105-113; Barsh et al., 1985 Proc. Natl. Acad. Sci. USA 82:2870-2874).
The complete cDNA sequence corresponding to the COL1A2 gene has been reported (Bernard et al., 1983, Biochem. 22:1139-1145; de Wet et al., 1987, J. Biol. Chem. 262:16032-16036; Kuivaniemi et al., 1988, Biochem. J. 252:633-640). Furthermore, the nucleot
Ala-Kokko Leena
Annunen Susanna
Colige Alain
Deltas Constantinos D.
Early James
Allegheny University of the Health Sciences
Horlick Kenneth R.
Morgan, Lewis & Bockius, L.L.P.
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