title: Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.
abstract: Familial dysautonomia (FD; also known as "Riley-Day syndrome"), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, to a 0.5-cM region on chromosome 9q31 and had shown that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its five genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a potential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific expression; and they also provide the basis for rapid carrier screening in the Ashkenazi Jewish population.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Slaugenhaupt
authors.forename: A
authors.initials: A
authors.lastname: Blumenfeld
authors.forename: S P
authors.initials: SP
authors.lastname: Gill
authors.forename: M
authors.initials: M
authors.lastname: Leyne
authors.forename: J
authors.initials: J
authors.lastname: Mull
authors.forename: M P
authors.initials: MP
authors.lastname: Cuajungco
authors.forename: C B
authors.initials: CB
authors.lastname: Liebert
authors.forename: B
authors.initials: B
authors.lastname: Chadwick
authors.forename: M
authors.initials: M
authors.lastname: Idelson
authors.forename: L
authors.initials: L
authors.lastname: Reznik
authors.forename: C
authors.initials: C
authors.lastname: Robbins
authors.forename: I
authors.initials: I
authors.lastname: Makalowska
authors.forename: M
authors.initials: M
authors.lastname: Brownstein
authors.forename: D
authors.initials: D
authors.lastname: Krappmann
authors.forename: C
authors.initials: C
authors.lastname: Scheidereit
authors.forename: C
authors.initials: C
authors.lastname: Maayan
authors.forename: F B
authors.initials: FB
authors.lastname: Axelrod
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D004402:Dysautonomia, Familial / Q000235:genetics*; D005091:Exons; D005819:Genetic Markers; D006801:Humans; D051550:I-kappa B Kinase; D008214:Lymphocytes / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012313:RNA / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D005819:Genetic Markers; D012313:RNA; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human