Method of diagnosing pulmonary hypertension

Abstract

This invention relates generally to a method of identifying an individual having an increased susceptibility to developing Familial Primary Pulmonary Hypertension (FPPH), as well as to a method for diagnosing an individual suffering from FPPH. The invention also relates to a method of identifying an individual having an increased susceptibility to developing (non-familial) Primary Pulmonary Hypertension (PPH), as well as to a method for diagnosing an individual suffering from PPH.

We claim:  
     
         1 . A method of identifying a subject having an increased susceptibility for developing pulmonary hypertension, comprising detecting a mutant Bone Morphogenic Protein Receptor II (BMPR-II) polypeptide or a mutated Bone Morphogenic Protein Receptor 2 (BMPR2) nucleic acid in the subject, thereby identifying a subject having an increased susceptibility for developing pulmonary hypertension.  
     
     
         2 . The method of  claim 1 , wherein the subject having an increased susceptibility for developing pulmonary hypertension is identified by detecting a mutated BMPR2 nucleic acid in the subject.  
     
     
         3 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid encodes a mutant BMPR-II polypeptide.  
     
     
         4 . The method of  claim 2  wherein the mutated BMPR2 nucleic acid comprises a missense mutation.  
     
     
         5 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid comprises a nonsense mutation.  
     
     
         6 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid comprises a deletion mutation.  
     
     
         7 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid comprises an insertion mutation.  
     
     
         8 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid comprises a truncation mutation.  
     
     
         9 . The method of  claim 8 , wherein the mutated BMPR2 nucleic acid is truncated at a nucleotide position of the sequence set forth in SEQ ID NO:1 which is 3′ to nucleotide position 2695.  
     
     
         10 . The method of  claim 2 , wherein the mutated BMPR2 nucleic acid comprises a nucleotide sequence that differs from the sequence set forth in SEQ ID NO:1.  
     
     
         11 . The method of  claim 1 , wherein the mutated BMPR2 nucleic acid or mutant BMPR-II polypeptide has a sequence associated with pulmonary hypertension.  
     
     
         12 . The method of  claim 11 , wherein the mutated BMPR2 nucleic acid comprises a mutation at a nucleotide position of the sequence set forth in SEQ ID NO:1 selected from the group consisting of 218, 354, 355, 367, 428, 504, 689, 958, 993, 1042, 1076, 1129, 1191, 1258, 1454, 1535, 1557, 1749, 2292, 2408, 2579, and 2695.  
     
     
         13 . The method of  claim 12 , wherein the mutation in the mutated BMPR2 nucleic acid results in a non-conservative substitution in the amino acid sequence encoded by the nucleic acid.  
     
     
         14 . The method of  claim 13 , wherein the mutation in the mutated BMPR2 nucleic acid results in a non-conservative substitution at a Cys residue encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         15 . The method of  claim 13 , wherein the mutation is selected from the group consisting of C218G, T354G, T367C, T367A, C428T, C993T, G1042A, T 1258 C, A 1454 G, A 1535 C, T 1557 A, C 2695 T.  
     
     
         16 . The method of  claim 1 , wherein the subject having an increased susceptibility for developing pulmonary hypertension is identified by detecting a BMPR2 nucleic acid having a sequence associated with pulmonary hypertension.  
     
     
         17 . The method of  claim 16 , wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension comprises a truncation mutation.  
     
     
         18 . The method of  claim 16 , wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension comprises a missense mutation.  
     
     
         19 . The method of  claim 16  wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension comprises a nonsense mutation.  
     
     
         20 . The method of  claim 16 , wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension comprises a deletion mutation.  
     
     
         21 . The method of  claim 16 , wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension comprises a nucleic acid sequence having an insertion mutation.  
     
     
         22 . The method of  claim 16 , wherein the BMPR2 nucleic acid having a sequence associated with pulmonary hypertension encodes a mutant BMPR-II polypeptide.  
     
     
         23 . The method of  claim 22 , wherein the mutant BMPR-II polypeptide comprises at least one mutation at an amino acid position of the sequence set forth in SEQ ID NO:2.  
     
     
         24 . The method of  claim 22 , wherein the BMPR-II polypeptide comprises at least one mutation at an amino acid position of the sequence set forth in SEQ ID NO:2 selected from the group consisting of 73, 118, 123, 143, 332, 348, 420, 485, 512, 519, and 899.  
     
     
         25 . The method of  claim 22 , wherein the BMPR-II polypeptide comprises at least one mutation at an amino acid position of the sequence set forth in SEQ ID NO:2 selected from the group consisting of a Trp residue at amino acid position 118, an Arg residue at amino acid position 123, a Ser residue at amino acid position 123, a Leu residue at amino acid position 143, an Ile residue at amino acid position 348, an Arg residue at amino acid position 420, an Ala residue at amino acid position 485, a Gln residue at amino acid position Gln, and a Lys residue at amino acid position 519.  
     
     
         26 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension terminates prematurely.  
     
     
         27 . The method of  claim 26 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension terminates at an amino acid position of the sequence set forth in SEQ ID NO:2 which is N-terminal to amino acid position 73, 332, or 899.  
     
     
         28 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one amino acid residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         29 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Cys residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         30 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Pro residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         31 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Lys residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         32 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Arg residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         33 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Asp residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         34 . The method of  claim 22 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Glu residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         35 . The method of  claim 1 , wherein the subject having an increased susceptibility for developing pulmonary hypertension is identified by detecting a mutant BMPR-II polypeptide in the subject.  
     
     
         36 . The method of  claim 35 , wherein the mutant BMPR-II polypeptide terminates prematurely.  
     
     
         37 . The method of  claim 36 , wherein the mutant BMPR-II polypeptide terminates at an amino acid position of the sequence set forth in SEQ ID NO:2 which is N-terminal to amino acid position 73, 332, or 899.  
     
     
         38 . The method of  claim 35 , wherein the mutant BMPR-II polypeptide comprises a non-conservative substitution at an amino acid position.  
     
     
         39 . The method of  claim 38 , wherein the mutant BMPR-II polypeptide comprises a non-conservative substitution for a Cys residue.  
     
     
         40 . The method of  claim 38 , wherein the non-conservative substitution is selected from the group consisting of a Trp residue at amino acid position 118, an Arg residue at amino acid position 123, a Ser residue at amino acid position 123, a Leu residue at amino acid position 143, an Ile residue at amino acid position 348, an Arg residue at amino acid position 420, an Ala residue at amino acid position 485, a Gln residue at amino acid position Gln, and a Lys residue at amino acid position 519.  
     
     
         41 . The method of  claim 35 , wherein the mutant BMPR-II polypeptide comprises an amino acid sequence that differs from the sequence set forth in SEQ ID NO:2.  
     
     
         42 . The method of  claim 41 , wherein the mutant BMPR-II polypeptide comprises a mutation at an amino acid position of the sequence set forth in SEQ ID NO:2 selected from the group consisting of 73, 118, 123, 143, 332, 348, 420, 485, 512, 519, and 899.  
     
     
         43 . The method of  claim 35 , wherein the BMPR-II polypeptide comprises at least one mutation at an amino acid position of the sequence set forth in SEQ ID NO:2 selected from the group consisting of 73, 118, 123, 143, 332, 348, 420, 485, 512, 519, and 899.  
     
     
         44 . The method of  claim 35 , wherein the BMPR-II polypeptide comprises at least one mutation at an amino acid position of the sequence set forth in SEQ ID NO:2 selected from the group consisting of a Trp residue at amino acid position 118, an Arg residue at amino acid position 123, a Ser residue at amino acid position 123, a Leu residue at amino acid position 143, an Ile residue at amino acid position 348, an Arg residue at amino acid position 420, an Ala residue at amino acid position 485, a Gln residue at amino acid position Gln, and a Lys residue at amino acid position 519.  
     
     
         45 . The method of  claim 1 , wherein the subject having an increased susceptibility for developing pulmonary hypertension is identified by detecting a BMPR-II polypeptide having a sequence associated with pulmonary hypertension in the subject.  
     
     
         46 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension terminates prematurely.  
     
     
         47 . The method of  claim 46 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension terminates at an amino acid position of the sequence set forth in SEQ ID NO:2 which is N-terminal to amino acid position 73, 332, or 899.  
     
     
         48 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one amino acid residue of a BMPR-II having the amino acid sequence set forth in SEQ ID NO:2.  
     
     
         49 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Cys residue of a BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         50 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Pro residue of the wild-type BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         51 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Lys residue of the wild-type BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         52 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Arg residue of the wild-type BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         53 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Asp residue of the wild-type BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         54 . The method of  claim 45 , wherein the BMPR-II polypeptide having a sequence associated with pulmonary hypertension has a non-conservative amino acid substitution of at least one Glu residue of the wild-type BMPR-II encoded by the nucleotide sequence set forth in SEQ ID NO:1.  
     
     
         55 . The method of  claim 1 , wherein the mutant BMPR-II polypeptide or mutated BMPR2 nucleic acid is due to a familial mutation.  
     
     
         56 . The method of  claim 1 , wherein the mutant BMPR-II polypeptide or mutated BMPR2 nucleic acid is due to a sporadic mutation.  
     
     
         57 . The method of  claim 1 , wherein the mutated BMPR2 nucleic acid has a sequence associated with pulmonary hypertension, wherein the mutated BMPR2 nucleic acid results in altered BMPR2 RNA function.  
     
     
         58 . The method of  claim 57 , wherein the altered BMPR2 RNA function is reduced BMPR2 mRNA production, altered processing of BMPR2 RNA, or increased BMPR2 RNA instability.  
     
     
         59 . The method of  claim 58 , wherein the altered BMPR2 RNA function is altered splicing of BMPR2 RNA.  
     
     
         60 . A kit for identifying a subject having an increased susceptibility for developing pulmonary hypertension, comprising reagents for detecting a mutant Bone Morphogenic Protein Receptor II (BMPR-II) polypeptide or a mutated BMPR2 nucleic acid in the subject.