# US 9,433,642 B2 · TRPC6 involved in glomerulonephritis

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- Number: US 9,433,642 B2
- Document ID: US9433642B2
- Status: Granted
- Kind: B2
- Application number: 12/782,075
- Filed: 2010-05-18
- Published: 2011-01-27
- Granted: 2016-09-06
- Earliest claimed: 2005-05-05
- Assignees: Duke University
- Applicants: Michelle Winn; Margaret A. Pericak-Vance; Jeffery M. Vance
- Inventors: Michelle Winn; Margaret A. Pericak-Vance; Jeffery M. Vance
- Web page: https://patentgrep.com/patent/US9433642B2

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- A61K 31/4174: Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
- A61K 31/69: Boron compounds
- A61K 33/24: Heavy metals; Compounds thereof
- A61P 13/12: of the kidneys
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2800/347: Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology and up to 20% of patients on dialysis have this diagnosis. A large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion channel protein Transient Receptor Potential Cation Channel 6. The missense mutation is a P112Q substitution, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II, and alters the intracellular distribution of TRPC6 protein. Previous work has emphasized the importance of cytoskeletal and structural proteins in proteinuric kidney diseases. Our findings suggest a novel mechanism for glomerular disease pathogenesis.

## Claims

### Claim 1

A cell-free preparation comprising one or more polynucleotides that encode a human Transient Receptor Potential Cation Channel, Subfamily C, Member 6 (TRPC6) polypeptide comprising the amino acid sequence of SEQ ID NO: 63 or 65, or a portion thereof, with the exception of a P112Q substitution relative to SEQ ID NO: 63 or 65, and wherein said one or more polynucleotides is amplifiable by one of the primer pairs SEQ ID NOs: 11 and 12; SEQ ID NOs: 13 and 14; SEQ ID NOs: 15 and 16; SEQ ID NOs: 17 and 18; SEQ ID NOs: 19 and 20; or SEQ ID NOs: 21 and 22, wherein said one or more polynucleotides comprise a heterologous detectably labeled moiety selected from the group consisting of enzymatic, radioactive, fluorescent and luminescent moieties.

### Claim 2 (depends on 1)

The cell-free preparation of claim 1, wherein said polynucleotide comprises an origin of replication.

### Claim 3 (depends on 1)

The cell-free preparation of claim 1, wherein said polynucleotide comprises a plasmid origin of replication.

### Claim 4 (depends on 1)

The cell-free preparation of claim 1, wherein said polynucleotide comprises a viral origin of replication.

### Claim 5

A cell-free preparation comprising a polynucleotide that encodes a human Transient Receptor Potential Cation Channel, Subfamily C, Member 6 (TRPC6) polypeptide comprising the amino acid sequence of SEQ ID NO: 63 or 65, or a portion thereof, with the exception of a P112Q substitution relative to SEQ ID NO:63 or 65, said polypeptide comprising at least six contiguous amino acid residues of the amino acid sequence set forth in SEQ ID NO:63 or 65, with the exception of a P112Q substitution relative to SEQ ID NO: 63 or 65, wherein said polynucleotide comprises a heterologous detectably labeled moiety selected from the group consisting of enzymatic, radioactive, fluorescent and luminescent moieties.

### Claim 6 (depends on 5)

The cell free preparation of claim 5, wherein said polynucleotide encodes a polypeptide comprising at least ten contiguous amino acid residues of the amino acid sequence set forth in SEQ ID NO: 63 or 65.

### Claim 7 (depends on 5)

The cell free preparation of claim 5, wherein said polynucleotide encodes a polypeptide comprising at least sixteen contiguous amino acid residues of the amino acid sequence set forth in SEQ ID NO: 63 or 65.

### Claim 8 (depends on 5)

The cell-free preparation of claim 5, wherein said one or more polynucleotides comprises TRPC6 cDNA.