Pkd mutations and evaluation of same

Abstract

The present invention relates to methods of detecting novel mutations in a PKD1 and/or PKD2 gene that have been determined to be associated with autosomal dominant polycystic kidney disease (ADPKD) in order to detect or predict the occurrence of ADPKD in an individual.

What is claimed is: 
     
         1 . A method of detecting or predicting the occurrence of autosomal dominant polycystic kidney disease (ADPKD) in an individual comprising detecting the presence of one or more nucleotide sequence alterations in a PKD1 gene having the nucleotide sequence of SEQ ID NO:1 or SEQ ID NO:7 in a nucleic acid sample obtained from said individual, wherein said one or more alterations are selected from the group consisting of: an insertion of CT at nucleotide position 1124 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 2291 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 2297 of SEQ ID NO:1, an insertion of a T at nucleotide position 5365 of SEQ ID NO:1, an insertion of a G at nucleotide position 6666 of SEQ ID NO:1, an insertion of an A at nucleotide position 6881 of SEQ ID NO:1, a deletion of a T at nucleotide position 8713 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 9134 of SEQ ID NO:1, an insertion of 5 nucleotides at nucleotide position 9536 of SEQ ID NO:1, a deletion of a T at nucleotide position 10239 of SEQ ID NO:1, a change of a C to an A at nucleotide position 483 of SEQ ID NO:1, a change of a C to an A at nucleotide position 7006 of SEQ ID NO:1, a change of a C to T at nucleotide position 8267 of SEQ ID NO:1, a change of a G to a Tat nucleotide position 8639 of SEQ ID NO:1, a change of a G to an A at nucleotide position 20168 of SEQ ID NO:7, a change of a G to a T at nucleotide position 31025 of SEQ ID NO:7, a change of a G to a C at nucleotide position 33415 of SEQ ID NO:7, a deletion of CAA between nucleotide positions 508 to 516 of SEQ ID NO:1, a deletion of TGG at nucleotide positions 1848 to 1850 of SEQ ID NO:1, a deletion of CCAACTCCG at nucleotide positions 8892 to 8900 of SEQ ID NO:1, a deletion of AAG at nucleotide positions 9905 to 9907 of SEQ ID NO:1, a deletion of CTC at nucleotide positions 10070 to 10072 of SEQ ID NO:1, a deletion of TGG at nucleotide positions 12597 to 12599 of SEQ ID NO:1, a change of a C to an A at nucleotide position 1023 of SEQ ID NO:1, a change of a G to an A at nucleotide position 385 of SEQ ID NO:1, a change of an A to a G at nucleotide position 1470 of SEQ ID NO:1, a change of a C to a T at nucleotide position 4262 of SEQ ID NO:1, a change of an A to a G at nucleotide position 1794 of SEQ ID NO:1, a change of a G to an A at nucleotide position 6036 of SEQ ID NO:1, a change of a C to a T at nucleotide position 2042 of SEQ ID NO:1, a change of a C to a Tat nucleotide position 3351 of SEQ ID NO:1, a change of an A to a G at nucleotide position 6756 of SEQ ID NO:1, a change of a C to a T at nucleotide position 5793 of SEQ ID NO:1, a change of a C to a T at nucleotide position 6707 of SEQ ID NO:1, a change of a G to a C at nucleotide position 10187 of SEQ ID NO:1, a change of a C to a G at nucleotide position 7116 of SEQ ID NO:1, a change of an A to a G at nucleotide position 10311 of SEQ ID NO:1, a change of a T to a Cat nucleotide position 7554 of SEQ ID NO:1, a change of a C to a T at nucleotide position 7757 of SEQ ID NO:1, a change of a T to a C at nucleotide position 8067 of SEQ ID NO:1, a change of a C to a Tat nucleotide position 8138 of SEQ ID NO:1, a change of a C to a T at nucleotide position 8509 of SEQ ID NO:1, a change of a C to an A at nucleotide position 10096 of SEQ ID NO:1 and a change of a C to a Tat nucleotide position 12658 of SEQ ID NO:1,
 wherein detection of said one or more nucleotide sequence alterations indicates that said individual has ADPKD or will develop ADPKD.   
     
     
         2 . The method of  claim 1 , wherein at least one nucleotide sequence alteration other than said one or more nucleotide sequence alterations listed in  claim 1  is also detected in a sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:4, wherein said at least one nucleotide sequence alteration is associated with ADPKD. 
     
     
         3 . The method of  claim 2 , wherein the presence of said one or more nucleotide sequence alterations in said nucleic acid sequence is detected by a method selected from the group consisting of sequencing, polymerase chain reaction (PCR), denaturing high performance liquid chromatography and combinations thereof. 
     
     
         4 . The method of  claim 2 , further comprising assessing the effect of said one or more nucleotide sequence alterations on a PKD1 gene product by assaying for at least one activity selected from the group consisting of expression of said PKD1 gene product and cleavage of said PKD1 gene product. 
     
     
         5 . A method of detecting or predicting the occurrence of autosomal dominant polycystic kidney disease (ADPKD) in an individual comprising detecting the presence of one or more nucleotide sequence alterations in a PKD2 gene having the nucleotide sequence of SEQ ID NO:4 in a nucleic acid sample obtained from said individual, wherein said one or more alterations are selected from the group consisting of: an insertion of: an A at nucleotide position 2226 of SEQ ID NO:4, a deletion of AG at nucleotide positions 2422 to 2423 of SEQ ID NO:4, a change of a C to a T at nucleotide position 2680 of SEQ ID NO:4, IVS7-1G>A, IVS8+5G>A, a deletion of TGG at nucleotide positions 374-376 of SEQ ID NO:4 and a deletion of TTC between nucleotide positions 1876-1881 of SEQ ID NO:4,
 wherein detection of said one or more nucleotide sequence alterations indicates that said individual has ADPKD or will develop ADPKD.   
     
     
         6 . The method of  claim 5  wherein at least one nucleotide sequence alteration other than said one or more nucleotide sequence alterations listed in  claim 5  is also detected in a sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:4, wherein said at least one nucleotide sequence alteration is associated with ADPKD. 
     
     
         7 . The method of  claim 5 , wherein the presence of said one or more nucleotide sequence alterations in said nucleic acid sequence is detected by a method selected from the group consisting of sequencing, polymerase chain reaction (PCR), denaturing high performance liquid chromatography and combinations thereof. 
     
     
         8 . The method of  claim 5 , further comprising assessing the effect of said one or more nucleotide sequence alterations on a PKD2 gene product by assaying for expression of said PKD2 gene product. 
     
     
         9 . A method for detecting in an individual the presence or absence of a mutant PKD gene comprising:
 a) obtaining a nucleic acid sample from said individual; and   b) detecting the presence or absence of one or more nucleotide sequence alterations in a PKD1 or PKD2 gene of said individual, wherein said one or more alterations are selected from the group consisting of: an insertion of CT at nucleotide position 1124 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 2291 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 2297 of SEQ ID NO:1, an insertion of a T at nucleotide position 5365 of SEQ ID NO:1, an insertion of a G at nucleotide position 6666 of SEQ ID NO:1, an insertion of an A at nucleotide position 6881 of SEQ ID NO:1, a deletion of a Tat nucleotide position 8713 of SEQ ID NO:1, an insertion of an A, T, G, or C at nucleotide position 9134 of SEQ ID NO:1, an insertion of 5 nucleotides at nucleotide position 9536 of SEQ ID NO:1, a deletion of a T at nucleotide position 10239 of SEQ ID NO:1, a change of a C to an A at nucleotide position 483 of SEQ ID NO:1, a change of a C to an A at nucleotide position 7006 of SEQ ID NO:1, a change of a C to T at nucleotide position 8267 of SEQ ID NO:1, a change of a G to a T at nucleotide position 8639 of SEQ ID NO:1, a change of a G to an A at nucleotide position 20168 of SEQ ID NO:7, a change of a G to a Tat nucleotide position 31025 of SEQ ID NO:7, a change of a G to a C at nucleotide position 33415 of SEQ ID NO:7, a deletion of CAA between nucleotide positions 508 to 516 of SEQ ID NO:1, a deletion of TGG at nucleotide positions 1848 to 1850 of SEQ ID NO:1, a deletion of CCAACTCCG at nucleotide positions 8892 to 8900 of SEQ ID NO:1, a deletion of AAG at nucleotide positions 9905 to 9907 of SEQ ID NO:1, a deletion of CTC at nucleotide positions 10070 to 10072 of SEQ ID NO:1, a deletion of TGG at nucleotide positions 12597 to 12599 of SEQ ID NO:1, a change of a C to an A at nucleotide position 1023 of SEQ ID NO:1, a change of a G to an A at nucleotide position 385 of SEQ ID NO:1, a change of an A to a G at nucleotide position 1470 of SEQ ID NO:1, a change of a C to a T at nucleotide position 4262 of SEQ ID NO:1, a change of an A to a G at nucleotide position 1794 of SEQ ID NO:1, a change of a G to an A at nucleotide position 6036 of SEQ ID NO:1, a change of a C to a T at nucleotide position 2042 of SEQ ID NO:1, a change of a C to a T at nucleotide position 3351 of SEQ ID NO:1, a change of an A to a G at nucleotide position 6756 of SEQ ID NO:1, a change of a C to a T at nucleotide position 5793 of SEQ ID NO:1, a change of a C to a Tat nucleotide position 6707 of SEQ ID NO:1, a change of a G to a Cat nucleotide position 10187 of SEQ ID NO:1, a change of a C to a G at nucleotide position 7116 of SEQ ID NO:1, a change of an A to a G at nucleotide position 10311 of SEQ ID NO:1, a change of a T to a C at nucleotide position 7554 of SEQ ID NO:1, a change of a C to a T at nucleotide position 7757 of SEQ ID NO:1, a change of a T to a Cat nucleotide position 8067 of SEQ ID NO:1, a change of a C to a T at nucleotide position 8138 of SEQ ID NO:1, a change of a C to a Tat nucleotide position 8509 of SEQ ID NO:1, a change of a C to an A at nucleotide position 10096 of SEQ ID NO:1 and a change of a C to a T at nucleotide position 12658 of SEQ ID NO:1, an insertion of: an A at nucleotide position 2226 of SEQ ID NO:4, a deletion of AG at nucleotide positions 2422 to 2423 of SEQ ID NO:4, a change of a C to a T at nucleotide position 2680 of SEQ ID NO:4, IVS7-1G>A, IVS8+5G>A, a deletion of TGG at nucleotide positions 374-376 of SEQ ID NO:4 and a deletion of TTC between nucleotide positions 1876-1881 of SEQ ID NO:4,   wherein detection of said one or more nucleotide sequence alterations is indicative of a mutant PKD gene.   
     
     
         10 . The method of  claim 9 , wherein the presence of one or more nucleotide sequence alterations in said PKD1 or PKD2 gene of said individual indicates that the individual has autosomal dominant polycystic kidney disease (ADPKD) or may develop ADPKD. 
     
     
         11 . The method of  claim 10 , wherein the presence or absence of said one or more nucleotide sequence alterations in said nucleic acid sequence is detected by a method selected from the group consisting of sequencing, polymerase chain reaction (PCR), denaturing high performance liquid chromatography and combinations thereof.