Human TRPCC cation channel and uses

Abstract

The present invention relates to all facets of a novel polynucleotide, TRPCC, the polypeptides it encodes, antibodies, and specific binding partners thereto, and their applications to research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are expressed in brain, kidney, pituitary, and other tissues, and are therefore useful in a variety of ways, including, but not limited to, as molecular markers, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing or treating, determining predisposition to brain and/or kidney disease, including diseases and conditions such as hypomagnesemia, hypocalcemia, and amyotrophic lateral sclerosis with frontotemporal dementia, etc.

1 . An isolated polynucleotide comprising, a polynucleotide sequence coding without interruption for a human TRPCC polypeptide, or complement thereto, 
 said TRPCC having 90% or more amino acid sequence identity along its entire length to the sequence comprising amino acids 1-690 of SEQ ID NO 2, and 90% or more amino acid sequence identity along its entire length to the sequence comprising from amino acids 691-1707 of SEQ ID NO 2,    and which has cation transport activity.    
     
     
         2 . An isolated polynucleotide of  claim 1 , 
 said TRPCC having 90% or more amino acid sequence identity along its entire length to the sequence comprising amino acids 1-690 of SEQ ID NO 2, and 95% or more amino acid sequence identity along its entire length to the sequence comprising from amino acids 691-1707 of SEQ ID NO 2.    
     
     
         3 . An isolated polynucleotide of  claim 1 , which codes for a human TRPCC of SEQ ID NO 2.  
     
     
         4 . An isolated polynucleotide of  claim 1 , which is SEQ ID NO 1.  
     
     
         5 . An isolated polynucleotide comprising a polynucleotide sequence coding for a human TRPCC polypeptide having 90% or more amino acid sequence identity along its entire length to the sequence coding for amino acids 1-690 of SEQ ID NO 2, or a fragment thereof, which polynucleotide is specific for said human TRPCC.  
     
     
         6 . An isolated polynucleotide of  claim 5 , wherein said fragment is effective in a polymerase chain reaction.  
     
     
         7 . An isolated polynucleotide of  claim 5  consisting essentially of a polynucleotide sequence coding for amino acids 1-690 of SEQ ID NO 2, or a fragment thereof.  
     
     
         8 . An isolated polynucleotide of  claim 5 , which is SEQ ID NO 6, 7, 8, or 9.  
     
     
         9 . An isolated human TRPCC polypeptide having an amino acid sequence of  claim 1 .  
     
     
         10 . An isolated human TRPCC polypeptide having the amino acid sequence of  claim 3 .  
     
     
         11 . An isolated human TRPCC polypeptide having an amino acid sequence of  claim 6 .  
     
     
         12 . An isolated human TRPCC polypeptide having an amino acid sequence of  claim 8 , or a fragment thereof which is specific for a human TRPCC.  
     
     
         13 . A method of detecting expression of a gene coding for human TRPCC, comprising, 
 contacting a sample comprising nucleic acid with a polynucleotide probe specific for a human TRPCC of  claim 1  under conditions effective for said probe to hybridize specifically with said human TRPCC, and    detecting hybridization between said probe and said human TRPCC.    
     
     
         14 . A method of  claim 14 , wherein said detecting is performed by: 
 Northern blot analysis, polymerase chain reaction (PCR), reverse transcriptase PCR, RACE PCR, or in situ hybridization.    
     
     
         15 . A method for identifying an agent that modulates the expression of a human TRPCC gene, or the biological activity of polypeptide encoded thereby, in cells expressing said gene, comprising, 
 contacting cells expressing human TRPCC of  claim 1  with a test agent under conditions effective for said test agent to modulate the expression of a gene coding for said human TRPCC, or the biological activity of a polypeptide encoded thereby, and    determining whether said test agent modulates said human TRPCC.    
     
     
         16 . A method of  claim 15 , wherein said agent is an antisense polynucleotide which is effective to inhibit translation of said human TRPCC.  
     
     
         17 . A method of detecting polymorphisms in human TRPCC comprising: 
 comparing the structure of: genomic DNA comprising all or part of human TRPCC, mRNA comprising all or part of human TRPCC, cDNA comprising all or part of human TRPCC, or a polypeptide comprising all or part of human TRPCC, with the complete structure of human TRPCC as set forth in SEQ ID NO 1 of  claim 1 .    
     
     
         18 . A method of  claim 17 , wherein said polymorphism is a nucleotide deletion, substitution, inversion, or transposition.  
     
     
         19 . A method of  claim 17 , wherein said polymorphism is a mutation associated with hypomagnesemia with hypocalcemia.  
     
     
         20 . A method of  claim 17 , wherein said polymorphism is a mutation associated with amyotrophic lateral sclerosis with frontotemporal dementia.  
     
     
         21 . A method of identifying a mutation associated with hypomagnesemia with hypocalcemia, comprising: 
 comparing the structure of: genomic DNA comprising all or part of human TRPCC, MRNA comprising all or part of human TRPCC, cDNA comprising all or part of human TRPCC, or a polypeptide comprising all or part of human TRPCC, with the complete structure of human TRPCC as set forth in SEQ ID NO 1 of  claim 1 , in a patient having hypomagnesemia with hypocalcemia, or a family member thereof.    
     
     
         22 . A method of identifying a mutation associated with amyotrophic lateral sclerosis with frontotemporal dementia, comprising: 
 comparing the structure of: genomic DNA comprising all or part of human TRPCC, mRNA comprising all or part of human TRPCC, cDNA comprising all or part of human TRPCC, or a polypeptide comprising all or part of human TRPCC, with the complete structure of human TRPCC as set forth in SEQ ID NO 1 of  claim 1 , in a patient having amyotrophic lateral sclerosis with frontotemporal dementia, or a family member thereof.    
     
     
         23 . A mammalian cell whose genome comprises a functional disruption of the human TRPCC gene of  claim 1  within a polynucleotide sequence coding for amino acid residues 1-690 of SEQ ID NO 2.  
     
     
         24 . A non-human, transgenic mammal comprising a cell of  claim 23 , which has a defect in calcium conductance.  
     
     
         25 . An antibody which is specific-for: 
 an epitope selected from a human TRPCC polypeptide of  claim 12 .    
     
     
         26 . A method of selecting a human TRPCC polynucleotide or amino acid sequence from a database, comprising: 
 displaying, in a computer-readable medium, a polynucleotide sequence or polypeptide sequence for human TRPCC of  claim 1 , or complements to the polynucleotides sequence, wherein said displayed sequences have been retrieved from said database upon selection by a user.