Corneodesmosin based test and model for inflammatory disease

Abstract

The present invention relates to a polynucleotide encoding the corneodesmosin protein having one or more nucleotide insertions, deletions, or substitutions at one or more novel positions. The invention also relates to the corneodesmosin protein having one or more amino acid insertions, deletions, and substitutions. These nucleotide and amino acid polymorphisms are useful in diagnosing or determining susceptibility to corneodesmosin-mediated disease, such as inflammatory diseases, including psoriasis, and in treating such disease. Host cells and transgenic non-human animals comprising polynucleotides or proteins of the invention are provided. Methods of screening for agents for use in treating corneodesmosin-mediated disease are also provided.

1 . A method comprising the detection of one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 4805 and 4875 of SEQ ID NO:1. 
     
     
         2 . The method of  claim 1  wherein the one or more variant alleles are selected from the group consisting of 4805AAG (insert), and G4875T. 
     
     
         3 . A method for diagnosing or determining susceptibility of a subject to a corneodesmosin-mediated disease comprising the detection of one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1. 
     
     
         4 . The method of  claim 3  wherein the one or more variant alleles are selected from C3339T, C3408T, 4805AAG (insert), and G4875T. 
     
     
         5 . The method of  claim 1  or  3  wherein the corneodesmosin-mediated disease is an inflammatory disease 
     
     
         6 . The method of  claim 1  or  3  wherein the corneodesmosin-mediated disease is psoriasis. 
     
     
         7 . The method of  claim 1  or  3  wherein detection of the one or more variant alleles is carried out using a polynucleotide isolated from a biological sample selected from the group consisting of whole blood, semen, saliva, tears, skin, hair, and a buccal sample. 
     
     
         8 . The method of  claim 1  or  3  wherein detection of the one or more variant alleles is carried out using an agent capable of detecting one or more of the variant alleles. 
     
     
         9 . The method of  claim 8  wherein the agent is an anti-sense polynucleotide that is complementary to one or more of the variant alleles or to a region flanking one or more of the variant alleles. 
     
     
         10 . The method of  claim 1  or  3  wherein detection of one or more of the variant alleles is carried out using a method selected from the group consisting of direct probing, allele specific hybridization, polymerase chain reaction (PCR), allele specific amplification (ASA), and restriction fragment length polymorphism (RFLP). 
     
     
         11 . The method of  claim 1  or  3  wherein detection of one or more of the variant alleles is carried out by detecting the presence of a variant protein. 
     
     
         12 . The method of  claim 11  wherein detection of the variant protein is carried out using an antibody to an antigen of the variant protein. 
     
     
         13 . An agent capable of detecting one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1. 
     
     
         14 . The agent of  claim 13  wherein the one or more variant alleles are selected from the group consisting of C3339T, C3408T, 4805AAG (insert), and G4875T. 
     
     
         15 . The agent of  claim 13  for use in a method for the diagnosis of or determining the susceptibility of a subject to a corneodesmosin-mediated disease. 
     
     
         16 . The agent of  claim 13  wherein the agent is:
 (a) an anti-sense polynucleotide that is complementary to one or more of the variant alleles or to a region flanking one or more of the variant alleles; or   (b) an antibody to an antigen of the protein expressed from one or more of the variant corneodesmosin genes.   
     
     
         17 . A method of screening for an agent capable of detecting one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1, wherein the method is selected from the group consisting of:
 (i) a method comprising the steps of contacting a putative agent with a polynucleotide comprising one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1, and monitoring the reaction there between; and   (ii) a method comprising the steps of contacting a putative agent with a protein expressed from one or more variant alleles of the corneodesmosin gene having an alteration at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1, and monitoring the reaction there between.   
     
     
         18 . The method of  claim 17  wherein the one or more variant alleles are selected from C3339T, C3408T, 4805AAG (insert), and G4875T. 
     
     
         19 . The method of  claim 17  further comprising:
 (a) contacting the putative agent with a polynucleotide having SEQ ID NO:1, and comparing the reaction between:
 (i) the putative agent and the polynucleotide comprising the variant allele; and 
 (ii) the putative agent and the polynucleotide having SEQ ID NO:1; or 
   (b) contacting the putative agent with a protein having SEQ ID NO:2 and comparing the reaction between:
 (i) the putative agent and the protein expressed from the polynucleotide comprising the variant allele; and 
 (ii) the putative agent and the protein having SEQ ID NO:2. 
   
     
     
         20 . The method of  claim 17  wherein the method is carried out by contacting the putative agent with a host cell or transgenic non-human animal comprising the polynucleotide comprising the variant allele or the polypeptide expressed from the polynucleotide comprising the variant allele. 
     
     
         21 . A kit for the detection of a variant allele in the corneodesmosin gene comprising an agent capable of detecting one or more variant alleles in the corneodesmosin gene at one or more nucleotide positions selected from the group consisting of 3339, 3408, 4805, and 4875 of SEQ ID NO:1. 
     
     
         22 . The kit of  claim 21  wherein the one or more variant alleles are selected from C3339T, C3408T, 4805AAG (insert), and G4875T. 
     
     
         23 . The kit of  claim 21  wherein the agent is selected from the group consisting of:
 (a) an anti-sense polynucleotide that is complementary to one or more of the variant alleles or to a region flanking one or more of the variant alleles;   (b) an antibody to an antigen of the protein expressed from the corneodesmosin gene comprising one or more of the variant alleles; and   (c) a restriction enzyme that is capable of detecting the presence of the polynucleotide comprising one or more of the variant alleles.   
     
     
         24 . The kit of  claim 21  further comprising means for the detection of a reaction selected from the group consisting of:
 (a) nucleotide detection means;   (b) labeled secondary antibodies; and   (c) size detection means.   
     
     
         25 . The kit of  claim 21  for use in a method for the diagnosis of or determining the susceptibility of a subject to a corneodesmosin-mediated disease, and further comprising a key correlating the presence of the one or more variant alleles with the presence of, or susceptibility to, corneodesmosin-mediated disease.