Gene for Identifying Individuals with Familial Dysautonomia

Abstract

This invention relates to methods and compositions for detecting mutations causing Familial Dysautonomia (FD), an Ashkenazi Jewish disorder characterized by widespread sensory and variable autonomic dysfunction. Previously, we mapped the FD gene, DYS, to a 0.5 cM region of chromosome 9q31. We sequenced the minimal candidate region and cloned and characterized its 5 genes. IKBKAP harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA from FD patients, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from patient lymphoblasts is primarily wild-type, whereas only deleted message is seen in RNA from isolated brain. The mutation associated with the minor haplotype is a missense (R696P) mutation in exon 19 that is predicted to disrupt a potential phosphorylation site.

1 . A kit for the detection of the FD2 mutation associated with Familial Dysautonomia in a sample from a human subject, said kit comprising an isolated oligonucleotide probe from the group consisting of (a) through (d) below:
 (a) an isolated oligonucleotide probe consisting of at least 16 contiguous nucleotides of the portion of SEQ ID NO:1 from nucleotide 32,642 to nucleotide 36,846 which includes position 33,714 of SEQ ID NO: 1 and being suitable for the detection of the FD2 mutation at position 33,714 of SEQ ID NO:1;   (b) the complement of an isolated oligonucleotide probe consisting of at least 16 contiguous nucleotides of the portion of SEQ ID NO:1 from nucleotide 32,642 to nucleotide 36,846 which includes position 33,714 of SEQ ID NO: 1 and being suitable for the detection of the FD2 mutation at position 33,714 of SEQ ID NO:1;   (c) an isolated oligonucleotide probe consisting of at least 16 contiguous nucleotides of the portion of SEQ ID NO:1 from nucleotide 32,642 to nucleotide 36,846 which includes position 33,714 of SEQ ID NO: 1 except that the nucleotide which is at the same position as position 33,714 of SEQ ID NO:1 is a cytosine and being suitable for the detection of the FD2 mutation at position 33,714 of SEQ ID NO:1; and   (d) the complement of an isolated oligonucleotide probe consisting of at least 16 contiguous nucleotides of the portion of SEQ ID NO:1 from nucleotide 32,642 to nucleotide 36,846 which includes position 33,714 of SEQ ID NO: 1 except that the nucleotide which is at the same position as position 33,714 of SEQ ID NO:1 is a cytosine and being suitable for the detection of the FD2 mutation at position 33,714 of SEQ ID NO:1.   
     
     
         2 . The kit of  claim 1 , wherein the isolated oligonucleotide probe is 16 nucleotides.