Cornulin (CRNN) Variants And Uses Thereof

Abstract

The disclosure provides nucleic acid molecules, including cDNA, comprising an alteration that encodes a loss-of-function cornulin (CRNN) protein. The disclosure also provides isolated and recombinant human loss-of-function cornulin protein variants that comprise a truncation at a position corresponding to position 79. The truncation, and the nucleic acid molecules encoding this change, associate with skin disorders such as, for example, psoriasis, eczema, or atopic dermatitis. The disclosure also provides methods for determining whether a subject has or has a risk of developing a skin disorder, based on the identification of such alterations in the nucleic acid molecules encoding CRNN. Subjects at risk for or who have a skin disorder may be treated with an agent effective to treat the skin disorder.

1 - 14 . (canceled) 
     
     
         15 . An alteration-specific probe or primer comprising a nucleic acid sequence which is complementary to a nucleic acid sequence of a nucleic acid molecule encoding a cornulin protein truncated at a position corresponding to position 79 according to SEQ ID NO:8, wherein the alteration-specific probe or primer comprises a nucleic acid sequence which is complementary to a portion of the nucleic acid molecule encompassing the codon which encodes a cysteine at the position corresponding to the position 69 according to SEQ ID NO:8. 
     
     
         16 - 20 . (canceled) 
     
     
         21 . A method of treating a subject with a therapeutic agent that treats or inhibits a skin disorder, wherein the subject has a skin disorder or is at risk of developing a skin disorder, the method comprising:
 determining whether the subject has a nucleic acid molecule encoding a loss-of-function cornulin protein by:
 obtaining or having obtained a biological sample from the subject; and 
 performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the nucleic acid molecule encoding the loss-of-function cornulin protein; and 
   administering or continuing to administer to the subject having a nucleic acid molecule encoding a loss-of-function cornulin protein the therapeutic agent that treats or inhibits the skin disorder;   wherein the presence of a genotype having a nucleic acid molecule encoding a loss-of-function cornulin protein indicates the subject has an increased risk of developing the skin disorder.   
     
     
         22 . The method according to  claim 21 , wherein the skin disorder is psoriasis, eczema, or atopic dermatitis. 
     
     
         23 . The method according to  claim 21 , wherein the loss-of-function cornulin protein is a truncated cornulin protein. 
     
     
         24 . The method according to  claim 23 , wherein the loss-of-function cornulin protein comprises a cysteine at the position corresponding to position 69 according to SEQ ID NO:8. 
     
     
         25 . The method according to  claim 23 , wherein the loss-of-function cornulin protein comprises a cysteine at the position corresponding to position 69 according to SEQ ID NO:8, and is truncated at a position corresponding to position 79 according to SEQ ID NO:8. 
     
     
         26 . The method according to  claim 25 , wherein the truncated cornulin protein comprises a different amino acid compared to the wild type cornulin protein at any one of the positions corresponding to positions 69 to 76, 78, and 79 according to SEQ ID NO:8. 
     
     
         27 . The method according to  claim 25 , wherein the truncated cornulin protein comprises the amino acid sequence of SEQ ID NO:10 at the positions corresponding to positions 69 to 79 according to SEQ ID NO:8. 
     
     
         28 . The method according to  claim 21 , wherein the loss-of-function cornulin protein comprises SEQ ID NO:8. 
     
     
         29 . The method according to  claim 21 , wherein the determining step comprises sequencing at least a portion of the nucleic acid molecule that encodes the loss-of-function cornulin protein, wherein the sequenced nucleic acid molecule encodes a cornulin protein truncated at a position corresponding to position 79 according to SEQ ID NO:8. 
     
     
         30 . The method according to  claim 29 , wherein the portion of the nucleic acid molecule sequenced comprises a plurality of positions encompassing the codon encoding the position corresponding to the position 69 according to SEQ ID NO:8. 
     
     
         31 . The method according to  claim 29 , wherein the determining step comprises sequencing the entire nucleic acid molecule encoding the loss-of-function cornulin protein. 
     
     
         32 . The method according to  claim 21 , wherein the determining step comprises:
 amplifying at least a portion of the nucleic acid molecule that encodes a cornulin protein, wherein the amplified nucleic acid molecule encompasses the codon encoding the amino acid at the position corresponding to position 69 according to SEQ ID NO:8;   labeling the amplified nucleic acid molecule with a detectable label;   contacting the labeled nucleic acid molecule with a support comprising a probe, wherein the probe comprises a nucleic acid sequence which specifically hybridizes under stringent conditions to a nucleic acid sequence encompassing the codon encoding a cysteine at the position corresponding to position 69 according to SEQ ID NO:8; and   detecting the detectable label.   
     
     
         33 . The method according to  claim 21 , wherein the determining step comprises:
 contacting a nucleic acid molecule that encodes a cornulin protein with a probe comprising a detectable label, wherein the probe comprises a nucleic acid sequence which specifically hybridizes under stringent conditions to a nucleic acid sequence encompassing the codon encoding cysteine at the position corresponding to position 69 according to SEQ ID NO:8; and   detecting the detectable label.   
     
     
         34 . The method according to  claim 21 , wherein the nucleic acid molecule encoding the loss-of-function cornulin protein is genomic DNA. 
     
     
         35 . The method according to  claim 34 , wherein the genomic DNA comprises SEQ ID NO:2. 
     
     
         36 . The method according to  claim 21 , wherein the nucleic acid molecule encoding the loss-of-function cornulin protein is mRNA. 
     
     
         37 . The method according to  claim 36 , wherein the mRNA comprises SEQ ID NO:4. 
     
     
         38 . The method according to  claim 21 , wherein the nucleic acid molecule encoding the loss-of-function cornulin protein is cDNA. 
     
     
         39 . The method according to  claim 38 , wherein the cDNA comprises SEQ ID NO:6. 
     
     
         40 . The method according to  claim 21 , wherein the therapeutic agent comprises a vitamin. 
     
     
         41 . The method according to  claim 40 , wherein the vitamin is Vitamin A or Vitamin D. 
     
     
         42 . The method according to  claim 21 , wherein the therapeutic agent is salicylic acid, eicosapentaenoic acid (EPA), psoralen, cyclosporine, methotrexate, or etanercept. 
     
     
         43 . The method according to  claim 21 , wherein the therapeutic agent is a corticosteroid. 
     
     
         44 . The method according to  claim 21 , wherein the therapeutic agent is an antibody. 
     
     
         45 . The method according to  claim 44 , wherein the antibody is adalimumab, brodalumab, ixekizumab, secukinumab, or ustekinumab.