Nephrin gene and protein

Details Nephrin gene and protein Nephrin gene and protein

1998-03-18

2001-03-27

Fredman, Jeffrey (Department: 1639)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S022100, C536S024300, C536S024310, C536S024320, C536S024330, C435S006120, C435S091200, C435S810000

Reexamination Certificate

active

06207811

ABSTRACT:

BACKGROUND OF THE INVENTION
Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1, MIM 256300) is an autosomal recessive disorder, and a distinct entity among congenital nephrotic syndromes. It is characterized by massive proteinuria at the fetal stage and nephrosis at birth. Importantly, NPHS1 appears to solely affect the kidney and, therefore, it provides a unique model for studies on the glomerular filtration barrier.
The primary barrier for ultrafiltration of plasma in renal glomeruli comprises three layers; a fenestrated endothelium, a 300-350 nm thick glomerular basement membrane (GBM), and slit pores, i.e. diaphragms located between the foot processes of the epithelial cells. This barrier is a highly sophisticated size-selective molecular sieve whose molecular mechanisms of function are still largely unclarified. It is anticipated that the GBM, a tightly cross-linked meshwork of type IV collagen, laminin, nidogen and proteoglycans, contains pores that restrict the penetration of large proteins and cells, and, additionally, it has been hypothesized that anionic heparan sulfate proteoglycan components contribute to an electric barrier for macromolecules (Kasinath and Kanwar, 1993). The glomerular filter is affected in a large number of acquired and inherited diseases resulting in extensive leakage of plasma albumin and larger proteins leading to nephrotic syndrome and end stage renal disease. Understanding of the molecular mechanisms of the glomerular filtration process and its pathology is of fundamental importance for clinical medicine, which, in turn, may facilitate novel developments for diagnosis and treatment of complications in primary and secondary diseases of the kidney. Genetic diseases with defects in the filtration barrier as major symptoms can serve as models for providing such knowledge.
Congenital nephrotic syndromes (NPHS) form a heterogenous group of diseases characterized by massive proteinuria at or shortly after birth (Rapola et al., 1992). Nephrotic syndrome can be primary, acquired, or a part of other syndromes. Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) is a distinct entity among NPHS. It is an autosomal recessive disorder with an incidence of 1:10,000 births in Finland, but considerably less in other countries (Norio, 1966; Huttunen, 1976). The disease manifests itself already at the fetal stage with heavy proteinuria in utero, demonstrating early lesions of the glomerular filtration barrier. The pathogenesis of NPHS1 has remained obscure. There are no pathognomonic pathologic features, the most typical histological finding of NPHS1 kidneys being dilation of the proximal tubuli (Huttunen et aL 1980). The kidneys are also large and have been found to contain a higher amount of nephrons than age-matched controls (Tryggvason and Kouvalainen, 1975). Electron microscopy reveals no abnormal features of the GBM itself, although there is a loss of foot processes of the glomerular epithelial cells, a finding characteristic for nephrotic syndromes of any cause. Analyses of GBM proteins, such as type IV collagen, laminin, and heparan sulfate proteoglycan have not revealed abnormal findings in NPHS1 (e.g. see Ljungberg et al. 1993, Kestilä et al. 1994a). NPHS1 is a progressive disease, usually leading to death during the first two years of life, the only life-saving treatment being kidney transplantation (Hohnberg et al. 1995). Importantly, most transplanted patients have, thus far, not developed extrarenal complications, suggesting that the mutated gene product is highly specific for kidney development and/or glomerular filtration function. However, about 20% of the patients have developed post-transplantation nephrosis the cause of which is unknown (Laine et al., 1993; Holmberg et al., 1995).
Due to its high specificity for the glomerular filtration process, NPHS1 provides a unique model disease for studies on this important kidney function. Since there was no strong candidate gene for the disease, we have used the positional cloning approach in our attempts to identify the CNF gene, and have localised the gene to a 150 kb region on chromosome 19q13.1 (Kestilä et al., 1994b; Männikkö et al., 1995). We have identified a novel gene in the critical region and shown it to be mutated in NPHS1. The gene product is a novel transmembrane protein, which in the human embryo shows a high expression level in renal glomeruli.
SUMMARY OF THE INVENTION
The present invention provides for the novel protein Nephrin and the gene encoding for this protein. The present invention encompasses a novel DNA nucleic acid sequence which is the nucleic acid sequence of SEQ ID NO:1 which encodes for the nephrin protein. The present invention also encompasses the protein encoded for by the coding regions of the nucleic acid sequence of SEQ ID NO:1 which has the amino acid sequence of SEQ ID NO:2. In particular, the present invention also encompasses the mature nephrin protein in which the signal peptide has been cleaved off.
The present invention encompasses method, reagents and kits for screening individuals for the presence of mutated Nephrin gene for diagnosis, pre-natal screening, or post-natal screening for susceptibility to glomerular nephrosis or basement membrane disease. In particular, the present invention provides for screening for congenital nephrotic syndromes of the Finnish type (NPHS1).
The present invention provides for methods, reagents and kits for the therapeutic treatment of basement membrane disease associated with defective endogenous Nephrin gene product. Thus the present invention provides for therapeutic treatment using Nephrin protein, and in particular using protein produced by recombinant DNA methods. In addition, the present invention provides for gene therapy using therapeutic nucleic acid constructs containing the Nephrin gene, or substantially similar DNA sequence thereto.


REFERENCES:
Altschul, S. F., Gish, W., Miller, W., Myers, E. W., and Lipman, D.J. (1990) Basic local alignment search tool. J. Mol. Biol. 215, 403-10.
Appel R.D., Bairoch, A. and Hochstrasser, D.F. (1994) A new generation of information retrieval tools for biologists: the example of the ExPASy WWW server. Trends Biochem. Sci. 19:258-260.
Barker, D., Hostikka, S.L., Zhou, J., Chow, L.T., Oliphant, A.R., Gerken, S.C., Gregory, M.C., Skolnick, M.H., Atkin, C.L. and Tryggvason, K. (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248, 1224-1227.
Brümmendott, T., and Rathjen, F.G. (1994) Cell adhesion molecules 1: Immunoglobulin superfamily. Protein profile 1, 951-1058.
Burge, C. and Karlin, S. (1997) Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78-94.
de la Chapelle, A. (1993) Disease gene mapping in isolated human populations: the example of Finland. J. Med. Genet. 30:857-865.
Dolan, M., Horchar, T., Rigatti, B., and Hassell, J.R. (1997) Identification of sites in domain I perlecan that regulate heparan sulfate synthesis. J. Biol. Chem. 272, 4316-4322.
Fahrig, T., Landa, C., Pesheva, P., Kühn, K., and Schacher, M. (1987) Characterization of binding properties of the myelin-associated glycoprotein to extracellular matrix constituents. EMBO J. 6, 2875-2883.
Fuchhuber, A., Niaudet, P., Gribouval, O., Genevieve, J., Gubler, M-C., Broyer, M. and Antignac, C. (1996) Congenital nephrotic syndrome of the Finnish type: linkage to the locus in a non-Finnish population. Pediatr. Nephrol. 10: 135-138.
Hästbacka, J., de la Chapelle, A., Mahtani, M.M., Clines, G., Reeve-Daly, M.P., Daly, M., Hamilton, B.A., Kusumi, K., Trivedi, B., Weaver, A., Coloma, A., Lovett, M., Buckler, A., Kaitila, I., and Lander, E.S. (1994) The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073-1087.
Holmberg, C., Antikainen, M., Rönnholm, K., Ala-Houhala, M. and Jalanko, H. (1995) Management of congenital nephrotic syndrome of the Finnish type. Pediatr. Nephrol. 9: 87-93.
Ikonen, E., Baumann, M., Grön, K., Syvänen, A-C., Enomaa,

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