Diabetes gene

Abstract

The present invention relates generally to the field of human genetics. Specifically, the present invention relates to methods and materials used to isolate and detect human diabetes mellitus predisposing gene, specifically the angiotensinogen (AGT) gene, some mutant alleles of which cause susceptibility to insulin-dependent diabetes mellitus (IDDM). More specifically, the invention relates to germline mutations in the AGT gene and their use in the diagnosis of predisposition to diabetes. The invention also relates to the prophylaxis and/or therapy of diabetes associated with a mutation in the AGT gene. The invention further relates to the screening of drugs for diabetes therapy. Finally, the invention relates to the screening of the AGT gene for mutations, which are useful for diagnosing the predisposition to diabetes.

1 . A nucleic acid selected from the group consisting of:
 (a) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, or complement thereof,   (b) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:2, or complement thereof,   (c) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:3, or complement thereof,   (d) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:4, or complement thereof,   (e) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:5, or complement thereof,   (f) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:8   (g) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:8, wherein G at nucleotide position 26 of the exon is substituted with T, or a complement thereof,   (h) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:8, wherein C at nucleotide position 96 of the exon is substituted with T, or a complement thereof,   (i) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:8, wherein T at nucleotide position 286 of the exon is substituted with C, or a complement thereof,   (j) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein C at nucleotide position 2201 is substituted with T, or a complement thereof   (k) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein T at nucleotide position 2271 is substituted with C, or a complement thereof   (l) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein G at nucleotide position 603 is deleted, or a complement thereof   (m) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein C at nucleotide position 2731 is substituted with T, or a complement thereof   (n) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein A at nucleotide position 2297 is substituted with G, or a complement thereof   (o) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein T at nucleotide position 2649 is substituted with A, or a complement thereof   (p) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein G at nucleotide position 2753 is substituted with A, or a complement thereof   (q) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein T at nucleotide position 2759 is substituted with C, or a complement thereof   (r) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:1, wherein G at nucleotide position 2829 is substituted with A, or a complement thereof   (s) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein T at nucleotide position 190 is substituted with C, or a complement thereof,   (t) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein C at nucleotide position 503 is substituted with T, or a complement thereof,   (u) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein G at nucleotide position 927 is substituted with A, or a complement thereof,   (v) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein C at nucleotide position 928 is substituted with T, or a complement thereof,   (w) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein G at nucleotide position 1093 is substituted with A, or a complement thereof,   (x) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein C at nucleotide position 1340 is substituted with T, or a complement thereof, and   (y) a DNA molecule comprising the nucleotides set forth in SEQ ID NO:7, wherein G at nucleotide position 1529 is substituted with T, or a complement thereof.   
     
     
         2 . A method for detecting an alteration in AGT wherein said alteration is associated with IDDM in a human, wherein said method comprises analyzing an AGT gene or an AGT gene expression product from a tissue of said human. 
     
     
         3 . A method as claimed in  claim 2  wherein the sequence of the AGT gene in said sample is compared with the sequence of one or more wild-type AGT gene sequences. 
     
     
         4 . The method of  claim 2  useful for determining whether a human subject has or is at risk for developing diabetes mellitus comprising the step of:
 a) obtaining a sample from a subject, said sample comprising nucleic acid molecules containing AGT gene; and   b) detecting the presence or absence of a genetic polymorphism in the gene of said subject, wherein the presence of said genetic polymorphism identifies a subject that has or is at risk for developing diabetes.   
     
     
         5 . The method of  claim 4  wherein said polymorphism is one of those specified in  claim 1 . 
     
     
         6 . A method of screening for drug candidates useful in treating diabetes resulting from a mutation in AGT, wherein said method involves mixing a mutant AGT in both the presence of a drug and the absence of said drug and measuring the level of the biological activity of the mutant AGT, wherein if the level of the biological activity is less in the presence of said drug than in the absence of said drug then said drug is a drug candidate for treating diabetes.