Familial Dysautonomia Is Caused by Mutations of the IKAP Gene

Am J Hum Genet. 2001 Mar;68(3):753-8. doi: 10.1086/318808. Epub 2001 Jan 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Carrier Proteins / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 9*
  • Consensus Sequence
  • Dysautonomia, Familial / genetics*
  • Exons
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Deletion
  • Transcriptional Elongation Factors

Substances

  • Carrier Proteins
  • Elp1 protein, human
  • Transcriptional Elongation Factors

Associated data

  • RefSeq/NM_003640