Animal Selected For Lacking Heparan Sulfate-3-O-Sulfotransferase-1 and Uses Thereof

Abstract

An animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity is provided. This animal exhibits characteristics associated with myxomatous valvular disease and is useful for identifying agents which prevent, delay or treat myxomatous valvular disease. Methods of diagnosing myxomatous valvular disease are also provided.

1 . An animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity, wherein said animal exhibits characteristics associated with myxomatous valvular disease.  
     
     
         2 . A method of producing an animal of  claim 1  comprising the steps of: 
 a) introducing a transgene containing 3-O-sulfotransferase-1 nucleic acid sequences and a selectable marker into a first and second isocongenic animal;    b) screening for the first and second isocongenic heterozygous animals which contain the transgene;    c) maintaining the first and second isocongenic heterozygous animals by backcrossing said animals to respective first and second inbred animals;    d) crossing the first and second isocongenic heterozygous animals to produce a homozygous knock-out animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity.    
     
     
         3 . A method of screening for an agent for treatment of myxomatous valvular disease comprising administering an agent to an animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity, wherein said animal exhibits characteristics of myxomatous valvular disease, and determining whether the agent at least partially abates at least one of the characteristics of myxomatous valvular disease in said animal.  
     
     
         4 . A method of screening for an agent that prevents or delays the development of myxomatous valvular disease comprising administering an agent to an animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity, wherein said animal is capable of exhibiting characteristics of myxomatous valvular disease and determining whether the agent at least partially prevents or delays the age of development of at least one of the characteristics of myxomatous valvular disease in said animal compared to the age of development of said characteristic in an untreated animal.  
     
     
         5 . A method of diagnosing a myxomatous valvular disease comprising detecting the level or mutation of heparan sulfate 3-O-sulfotransferase-1 in a sample wherein a mutation or decrease in the level of heparan sulfate 3-O-sulfotransferase-1 is indicative of a myxomatous valvular disease.  
     
     
         6 . The method of  claim 5 , wherein detecting the level of heparan sulfate 3-O-sulfotransferase-1 comprises contacting a sample with an antibody which specifically binds heparan sulfate 3-O-sulfotransferase-1 so that said antibody binds to the heparan sulfate 3-O-sulfotransferase-1; detecting bound antibody; and comparing the level of the heparan sulfate 3-O-sulfotransferase-1 to a known standard.  
     
     
         7 . The method of  claim 5 , wherein detecting the level of heparan sulfate 3-O-sulfotransferase-1 comprises evaluating the level of heparan sulfate 3-O-sulfotransferase-1 activity and comparing the heparan sulfate 3-O-sulfotransferase-1 activity level in the sample with a known standard.  
     
     
         8 . The method of  claim 5 , wherein detecting the level of heparan sulfate 3-O-sulfotransferase-1 comprises evaluating the level of RNA transcript encoding heparan sulfate 3-O-sulfotransferase-1 protein and comparing the heparan sulfate 3-O-sulfotransferase-1 RNA transcript level in the sample with a known standard.  
     
     
         9 . A kit for detecting the level of heparan sulfate 3-O-sulfotransferase-1 comprising an antibody which specifically binds heparan sulfate 3-O-sulfotransferase-1.  
     
     
         10 . A method of producing an antibody to heparan sulfate 3-O-sulfotransferase-1 protein comprising immunizing an animal selected for lacking heparan sulfate 3-O-sulfotransferase-1 activity with a heparan sulfate 3-O-sulfotransferase-1 polypeptide or antigenic fragment thereof, so that an antibody to heparan sulfate 3-O-sulfotransferase-1 is produced.