Familial Dysautonomia Is Caused by Mutations of the IKAP Gene

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 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.

Axon Transport and Neuropathy

“…FD is caused by a homozygous splice-site mutation in the Elp1/IKBKAP gene which leads to exon 20 skipping and nonsense-mediated degradation of the truncated protein 96,97 ( Figure 1A). It is characterized by debilitating sensory and widespread sympathetic nervous system dysfunction that involves the cardiovascular, renal, gastrointestinal, and pulmonary systems.…”

Molecular screening for diseases frequent in Ashkenazi Jews: Lessons learned from more than 100,000 tests performed in a commercial laboratory

“…19,24,25 Familial dysautonomia Also known as Riley-Day syndrome, FD is a protean disorder characterized by decreased sensitivity to pain and temperature, cardiovascular instability, recurrent pneumonias, vomiting crises, and gastrointestinal dysfunction. 26 A single intronic mutation in the IKBKAP gene (2507ϩ6 TϾC) accounts for more than 99% of AJ FD chromosomes. 26,27 Table 9 is a compilation of the 9,703 genotypes performed by our laboratory and also shows two published reports.…”

“…26 A single intronic mutation in the IKBKAP gene (2507ϩ6 TϾC) accounts for more than 99% of AJ FD chromosomes. 26,27 Table 9 is a compilation of the 9,703 genotypes performed by our laboratory and also shows two published reports. We observed a frequency of 1:42, only slightly lower than the frequency found in the Dor Yeshorim and New York populations of 1:30 and 1:32, respectively.…”

Screening of substrate peptide sequences for tissue-type transglutaminase (TGase 2) using T7 phage cDNA library

“…The protein band corresponding to IKAP is indicated by arrowhead et al 2009). Additionally, loss of function mutations in this gene cause familial dysautonomia (FD), with defective neuronal development (Slaugenhaupt et al 2001;Anderson et al 2001). In this mutation, the truncated form was expressed in which the C-terminal half region (572-1,332) was deleted by aberrant splicing due to a single point mutation.…”