Familial Dysautonomia Is Caused by Mutations of the IKAP Gene

Sylvia L. Anderson,¹ Rocco Coli,¹ Ira W. Daly,¹ Elizabeth A. Kichula,¹ Matthew J. Rork,¹ Sabrina A. Volpi,¹ Josef Ekstein,² and Berish Y. Rubin<sup>1

1</sup>Department of Biological Sciences, Fordham University, Bronx, NY; and ²Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY/Jerusalem

Received December 21, 2000; accepted for publication January 10, 2001; electronically published January 22, 2001.

Abstract

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 IB kinase complexassociated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein. Sequence analysis reveals a TC 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.