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 identification. 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 IkappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein. Sequence analysis reveals a T-->C transition in the donor splice site of intron 20. In individuals bearing a minor FD haplotype, a missense mutation in exon 19 disrupts a consensus serine/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 predicted carrier frequency of FD. These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD.

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@article{Anderson2001FamilialDI, title={Familial dysautonomia is caused by mutations of the IKAP gene.}, author={Shannon L. Anderson and Rocco Coli and Irene Daly and Elizabeth Kichula and M J Rork and Sabrina A Volpi and Josef Ekstein and Berish Y. Rubin}, journal={American journal of human genetics}, year={2001}, volume={68 3}, pages={753-8} }