Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Transferase other than ribonuclease
Reexamination Certificate
2001-07-02
2004-11-16
Saidha, Tekchand (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Transferase other than ribonuclease
C435S252300, C435S320100, C536S023200, C424S192100
Reexamination Certificate
active
06818428
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout the application various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains.
1. The Field of the Invention
This invention relates to the medical arts. In particular, it relates to a genetic marker that is useful for diagnosing or treating spondyloepimetaphyseal dysplasia and for identifying genetic carriers of heritable alleles associated with spondyloepimetaphyseal dysplasia.
2. Discussion of the Related Art
Osteochondrodysplasias are a genetically heterogeneous group of disorders related to cartilage producing cells. Abnormalities in cartilage formation can cause defects in bone deposition, skeletal development, linear growth, and the continued maintenance of cartilage and bone. (Reviewed in Mundlos, S. and Olsen, B. R.,
Heritable diseases of the skeleton. Part II: Molecular insights into skeletal development
-
matrix components and their homeostasis
, FASEB J. 11(4):227-33 [1997]).
There are numerous and disparate causes of osteochondrodysplasias. (Horton, W. A.,
Molecular genetic basis of the human chondrodysplasias
, Endocrinol. Metab. Clin. North Am. 25(3):683-97 [1996]). A significant number are due to defects in the collagen genes themselves. (Reviewed in Williams, C. J. and Jiminez, S. A.,
Heritable diseases of cartilage caused by mutations in collagen genes
, J. Rheumatol. Suppl. 43:28-33 [1995]; Byers, P. H.,
Molecular genetics of chondrodysplasias, including clues to development, structure, and function
, Curr. Opin. Rheumatol. 6(3):345-50 [1994]). In addition to collagen defects, several forms of osteochondrodysplasias are caused by mutations in the cartilage oligomeric matrix protein (COMP). (Ikegawa, S., et al.,
Novel and recurrent COMP mutations in preudoachondroplasia and epiphyseal dysplasia
, Hum. Genet. 103(6):633-8 [1998]; Briggs, M. D., et al.,
Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia
-
multiple epiphyseal dysplasia disease spectrum
, Am. J. Hum. Genet. 62(2):311-9 [1998]; Briggs, M. D., et al.,
Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage matrix protein gene
, Nat. Genet. 10(3):330-6 [1995]; Ballo, R., et al.,
Multiple epiphyseal dysplasia, ribbing type: a novel point mutation in the COMP gene in a South African family
, Am. J. Med. Genet. 68(4):396-400 [1997]).
Still other osteochondrodysplasias have been found to be caused by defects in secreted peptide growth factors and their receptors. (E.g., Thomas, J. T., et al.,
A human chondroplysplasia due to a mutation in a TGF
-&bgr;
superfamily member
, Nat. Genet. 12(3):315-7 [1996]; Bonaventure, J., et al.,
Common mutations in the gene encoding FGFR
-3
account for achondroplasia, hypochondroplasia and thanatophoric dysplasia
, Acta Paediatr. Suppl. 417:33-38 [1996]).
Finally, mutations in genes which affect protein sulfation cause some forms of osteochondrodysplasia. Protein sulfation is a post-translational modification carried out by all cells. (Lipmann, F.,
Biological sulfate activation and transfer
, Science 128:575-580 [1958]). The primary source of sulfur for the sulfation pathway is free sulfate, which can be transported into the cytoplasm by one of a variety of transmembrane symporter or antiporter molecules. (Elgavish, A., et al.,
Sulfate transport in human lung fibroblasts
(IMR-90), J. Cell Physiol. 125:243-250 [1985]; Markovich, D., et al.,
Expression cloning of rat renal Na+/SO
4
(2−)
cotransport
, Proc. Natl. Acad. Sci. U.S.A. 90:8073-8077 [1993]; Bissig, M., et al.,
Functional expression cloning of the canalicular sulfate transport system of rat hepatocytes
, J. Biol.Chem. 269:3017-3021 [1994]; Hastbacka, J., et al.,
The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine
-
structure linkage disequilibrium mapping
, Cell 78:1073-1087 [1994]; Everett, L. A., et al.,
Pendred syndrome is caused by mutations in a putative sulphate transporter gene
(PDS), Nat. Genet. 17:411-422 [1997]).
Within the cytoplasm, sulfate is activated to a high energy form in two enzymatic steps (Geller, D. H., et al.,
Co
-
purification and characterization of ATP
-
sulfurylase and adenosine
-5′-
phosphosulfate kinase from rat chondrosarcoma
, J. Biol. Chem. 262:7374-7382 [1987]). First, utilizing ATP and sulfate as substrates, an ATP sulfurylase activity catalyzes the synthesis of adenosine 5′-phosphosulfate (APS). Subsequently, an APS kinase activity catalyzes the phosphorylation of the APS to generate 3′-phosphoadenosine 5′-phosphosulfate (PAPS). PAPS is the universal bioactivated sulfate donor used in all known post-translational sulfation reactions.
Secreted extracellular matrix proteins are post-translationally sulfated in the Golgi, and delivery of PAPS to the Golgi is mediated by a PAPS translocase activity. Microsomal proteins with PAPS binding activity have been identified (Mandon, E. C., et al.,
Purification of the golgi adenosine
3′-
phosphate
5′-
phosphosulfate transporter, homodimer within the membrane
, Proc. Natl. Acad. Sci. U.S.A. 91:10707-10711 [1994]; Ozeran, J. D., et al.,
Kinetics of PAPS translocase: evidence for an antiport mechanism
, Biochemistry 35:3685-3694 [1996]), but the tissue specificity and the contribution of these proteins to PAPS transport remains unknown. Following transport, sulfation reactions are carried out by substrate-specific sulfotransferases. A major class of sulfation substrates within the Golgi is the side-chains of proteoglycans, which are abundant structural proteins of the extracellular matrices of many tissues. Proteoglycans are particularly abundant in the extracellular matrix of cartilage.
Direct evidence that sulfation of extracellular matrix proteins is essential for proper matrix function was revealed by the identification of mutations in the diastrophic dysplasia sulfate transporter, DTDST. (Hastbacka et al. [1994]). Mutations in the DTDST gene produce a spectrum of recessively inherited osteochondrodysplasia phenotypes. (Hastbacka et al. [1994]; Hastbacka, J., et al.,
Atelosteogenesis type II is caused by mutations in the diastrophic dyplasia sulfate transporter gene
(
DTDST
):
Evidence for a phenotypic series involving three chondrodysplasias
, Am. J. Hum. Genet. 58:255-262 [1996]; Superti-Furga, et al.,
A family of chondrodysplasias caused by mutations in the diastrophic dysplasia transporter gene and associated with impaired sulfation of proteoglycans
, Ann. N.Y. Acad. Sci. 785:195-201 [1996]). The severity of the three known disorders, i.e., the moderately severe diastrophic dysplasia phenotype and the lethal forms, atelosteogenesis type II and achondrogenesis type IB, is correlated with the consequences of the mutations on the activity of the transporter. (Superti-Furga, A, et al.
Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulfate transporter gene
, Nature Genet. 12:100-02 (1996). The mutations lead to dramatically reduced proteoglycan sulfation in cartilage, particularly the chondroitin sulfate side chains of aggrecan. However, even in the most severe disorder in the group, some proteoglycan sulfation can be measured. (Rossi A., et al.,
Undersulfation of proteoglycans synthesized by chondrocytes from patient with achondrogenesis type
1
B homozygous for an L
483
P substitution in the diastrophic dysplasia sulfate transporter
, J. Biol. Chem. 271:18456-64 [1996]; Rossi, A., et al.,
Undersulfation of cartilage proteoglycans ex vivo and increased contribution of amino acid sulfur to sulfation in vitro in McAlister dysplasia/atelosteogenesis type
2
Cohn Daniel H.
Faiyaz-Ul-Haque Muhammad
King Lily
Krakow Deborah
Cedars Sinai Medical Center
Perkins Coie LLP
Saidha Tekchand
LandOfFree
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