Human sodium-dependent phosphate cotransporter

Details Human sodium-dependent phosphate cotransporter Human sodium-dependent phosphate cotransporter

1999-09-08

2001-12-04

Prouty, Rebecca E. (Department: 1652)

Chemistry: analytical and immunological testing

Peptide, protein or amino acid

C514S012200, C530S350000

Reexamination Certificate

active

06326207

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a novel human sodium-dependent phosphate cotransporter and to the use of these sequences in the diagnosis, prevention, and treatment of diseases associated with increased or decreased phosphate levels.
BACKGROUND OF THE INVENTION
Phosphate is present in the plasma, intracellular fluid, cell membranes, collagen and bone tissue of mammals. It is a dynamic constituent of energy metabolism, an essential component of skeletal mineralization, a modulator of tissue concentrations of calcium, and plays a major role in renal excretion of H
+
.
Phosphate homeostasis in mammals is a balance between intake, intestinal absorption, bone deposition/resorption, and renal excretion and resorption. An excess of phosphate reduces the circulating Ca
2+
levels, and a deficit results in decreases in erythrocyte ATP and 2,3-diphosphoglycerate and contributes to the pathology of osteomalacia, hypocalciuria, and rickets. Dietary phosphate is absorbed from the gastrointestinal tract in an active, energy-dependent process that is modified by hormones, vitamin D, Ca
2+
, and Al
3+
. Regulation of the serum concentration of phosphate is maintained through resorption by the sodium phosphate cotransport system, located in the proximal convoluted renal tubule. Local concentration of phosphate in specific tissue types, such as liver, bone, and brain, is modulated by sodium phosphate transport proteins located in these tissues. (Hartmann, C. et al. (1996) Proc. Natl. Acad. Sci. 93:7409-7414; Glinn, M. et al.(1995) J. Neurochem. 65:2358-2365).
Human NPT1, NPT2, NaP
1
-3, and the X-linked hypophosphatemia (PEX) sodium phosphate transport proteins are found in the renal brush border membrane where they participate in renal tubular phosphate uptake. Although similar in function, these renal proteins differ in affinity, capacity, map to different chromosomal locations, and are differentially regulated by hormones and dietary phosphate (Tenenhouse, H. (1989) Biochem. Biophys. Acta 984: 207-213; Fulceri, R. (1993) Biochem. J. 289:299-306; Chong, S. et al. (1993) Genomics 18:355-359; Miyamoto, K. et al. (1995) Biochem. J. 305:81-85).
Sodium phosphate transport proteins in rat brain neurons regulate intracellular phosphate concentrations necessary for maintaining the phosphorylation potential of the cell. Physiological concentrations of phosphate enhance the ATP-dependent binding of Ca
2+
to brain microsomes, resulting in a larger intracellular pool of Ca
2+
released by inositol triphosphate. The expression of the brain specific sodium-dependent phosphate transporter, rBNPI, is developmentally regulated and is specific to neuron enriched regions of the adult rat brain. Avian osteoclasts express a sodium-dependent phosphate transporter regulated through integrin-mediated pathways in the presence of bone. This transporter is hypothesized to act in the transcellular movement of phosphate during active bone resorption (Ni, B. (1995) J. Neurosci. 15: 5789-5799; Gupta, A. (1996) Kidney Int. 46: 968-974).
By low stringency screening of a human kidney cortex cDNA library with a rabbit NaP1-1 cDNA, Chong et.al. (1993, supra) isolated a cDNA encoding a human sodium-dependent phosphate transport protein (NPT1). Localization of NPT1 to 6p23-p21.3 was found by Southern hybridization to HindIII-digested DNA from a human chromosome 6 somatic cell hybrid deletion panel. Fluorescence in situ hybridization maps NPT1 to 12p11 in the rabbit. This assignment agrees with the previously reported homology between rabbit chromosome 12 and human chromosome 6 (Kos, C. et al. (1994) Genomics 19: 176-177).
The discovery of proteins related to human renal sodium phosphate transport protein, and the polynucleotides encoding them, satisfies a need in the art by providing new compositions useful in diagnosis and treatment of diseases associated with increased or decreased phosphate levels.
SUMMARY OF THE INVENTION
The present invention features a novel human sodium-dependent phosphate cotransporter hereinafter designated NAPTR and characterized as having similarity to human renal sodium phosphate transport protein and rat brain-specific sodium-dependent inorganic phosphate cotransporter.
Accordingly, the invention features a substantially purified NAPTR having the amino acid sequence shown in SEQ ID NO: 1.
One aspect of the invention features isolated and substantially purified polynucleotides that encode NAPTR. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:2.
The invention also relates to a polynucleotide sequence comprising the complement of SEQ ID NO:2 or variants thereof In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2.
The invention additionally features nucleic acid sequences encoding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that encode NAPTR. The present invention also features antibodies which bind specifically to NAPTR, and pharmaceutical compositions comprising substantially purified NAPTR. The invention also features agonists and antagonists of NAPTR. The invention also features a method for treating disorders associated with decreased phosphate levels by administering NAPTR and a method for treating disorders associated with increased phosphate levels by administering an antagonist to NAPTR.


REFERENCES:
patent: 5872237 (1999-02-01), Feder et al.
patent: WO 98/14466 (1998-04-01), None
Gasparini, Direct Submission, 1997, GenBank Accession No. HSZ83953.*
Hartmann, C.M., et al., “Structure of murine and human renal type II Na+-phosphate cotransporter genes (Npt2 and NPT2).”Proc.Natl.Acad.Sci.USA(1996) 93:7409-7414.
Glinn, M., et al., “Characterization of Na(+)-dependent phosphate uptake in cultured fetal rat cortical neurons.”J.Neurochem.(1995) 65:2358-2365.
Tenenhouse, H.S., et al., “Effect of phosphonoformic acid, dietary phosphate and the Hyp mutation on kinetically distinct phosphate transport processes in mouse kidney.”Biochim.Biophys.Acta(1989) 984(2):207-213.
Fulceri, R., et al., “Physiological concentrations of inorganic phosphate affect MgATP-dependent Ca2+ storage and inositol trisphosphate-induced Ca2+ efflux in microsomal vesicles from non-hepatic cells.”Biochem.J.(1993) 289 (Pt 1):299-306.
Chong, S.S., et al., “Molecular Cloning of the cDNA Encoding a Human Renal Sodium Phosphate Transport Protein and Its Assignment to Chromosome 6p21.3-p23.”Genomics(1993) 18:355-359. (GI 450532).
Miyamoto, K., et al., “Cloning and functional expression of a Na+-dependent phosphate co-transporter from human kidney: cDNA cloning and functional expression.”Biochem.J.(1995) 305:81-85.
Ni B., et al., “Regional expression and cellular localization of the Na (+)-dependent inorganic phosphate cotransporter of rat brain”,Journal of Neuroscience,15 (8): 5789-5799 (1995).
Gupta, A., et al., “Phosphate transport in osteoclasts: a functional and immunochemical characterization.”Kidney Int.(1996) 49:968-974.
Kos, C.H., et al., “Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35.”Genomics(1994) 19:176-177.
Chong, S.S., et al. (GI 450532), GenBank Sequence Database (Accession X71355), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, 20894.
Chong, S.S., et al. (GI 450531), GenBank Sequence Database (Accession X71355), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, 20894. (GI 450532).
Ni, B., et al. (GI 507415), GenBank Sequence Database (Accession U07609), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, 20894.
Ni, B., et al. (GI 507414), GenBank Sequence Database (Accession U07609), National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, 20894. (GI 5074

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