Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia

Familial dysautonomia (FD; also known as "Riley-Day syndrome"), an Ashkenaz i Jewish disorder, is the best known and most frequent of a group of congen ital sensory neuropathies and is characterized by widespread sensory and va riable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, t o 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 an cestral haplotype. To investigate the molecular basis of FD, we sequenced t he minimal candidate region and cloned and characterized its five genes. On e of these, IKBKAP, harbors two mutations that can cause FD. The major hapl otype mutation is located in the donor splice site of intron 20. This mutat ion can result in skipping of exon 20 in the mRNA of patients with FD, alth ough they continue to express varying levels of wild-type message in a tiss ue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from b rain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a pot ential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific ex pression; and they also provide the basis for rapid carrier screening in th e Ashkenazi Jewish population.