Familial dysautonomia is caused by mutations of the IKAP gene

The defective gene DYS, which is responsible for familial dysautonomia (FD) and has been mapped to a 0.5-cM region on chromosome 9q31, has eluded iden tification. We identified and characterized the RNAs encoded by this region of chromosome 9 in cell lines derived from individuals homozygous for the major FD haplotype, and we observed that the RNA encoding the I kappaB kina se complex-associated protein (IKAP) lacks exon 20 and, as a result of a fr ameshift, encodes a truncated protein. Sequence analysis reveals a T-->C tr ansition in the donor splice site of intron 20. In individuals bearing a mi nor FD haplotype, a missense mutation in exon 19 disrupts a consensus serin e/threonine kinase phosphorylation site. This mutation results in defective phosphorylation of IKAP. These mutations were observed to be present in a random sample of Ashkenazi Jewish individuals, at approximately the predict ed carrier frequency of FD. These findings demonstrate that mutations in th e gene encoding IKAP are responsible for FD.