title: 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.
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Anderson
authors.forename: R
authors.initials: R
authors.lastname: Coli
authors.forename: I W
authors.initials: IW
authors.lastname: Daly
authors.forename: E A
authors.initials: EA
authors.lastname: Kichula
authors.forename: M J
authors.initials: MJ
authors.lastname: Rork
authors.forename: S A
authors.initials: SA
authors.lastname: Volpi
authors.forename: J
authors.initials: J
authors.lastname: Ekstein
authors.forename: B Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D016384:Consensus Sequence; D004402:Dysautonomia, Familial / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D035602:Transcriptional Elongation Factors