Familial Dysautonomia

Clincians

Familial Dysautonomia (FD) (also Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a recessive disease that is caused by loss of function of the I-kappa-B kinase complex associated protein (IKBKAP). In the Ashkenazi Jewish population, the incidence is 1/3600 in live birth (carrier frequency 1:30). Affected children show abnormal development of the nervous system that is associated with demyelination in various regions. This leads to a large clinical spectrum that includes vomiting crises, unsteady gait, and decreased perception of pain.

Molecular cause and consequences

In more than 99.5% of FD patients the 5’ splice site of exon 20 is mutated T->C in position 6 of intron 20. This point mutation interrupts base pairing with U1snRNA. U1 snRNA interacts both with the last three nucleotides of the exon and the first six nucleotides of the downstream intron. The majority of 5’ splice sites show complementarity to seven base pairs of U1 snRNA, that is there are mostly three mismatches between the 5’ splice site and U1 snRNA.

Bioinformatic analyses indicate that these mismatches are not randomly distributed. They either weaken the exonic portion of the 5’ splice site, which is then compensated by strong binding to the intronic portion, or a weak intronic portion is compensated by a strong exonic portion.

In exon 20 of the IKBKAP gene, the exonic part of the splice site is weak, due to an A at position –1. The T->C mutation weakens the intronic part of the 5’ splice site, which causes exon skipping. Exon 20 usage is susceptible to a weak 5’ splice site, as the exon has a weak 3’ splice site that has an A at the –3 position, and contains several exonic silencer elements.

Array analysis indicates that IKBKAP promotes expression of genes involved in oligodendrocyte and myelin formation, which could explain the demyelination phenotype caused by the loss of IKBKAP.

Gene's structure and Alternative Splicing (AS) events

View the full gene diagram and AS pattern of IKBKAP on the Fast DB website.

Molecular approaches to diagnoses and therapy

There is no definite treatment at present for Familial Dysautonomia. Some therapies under investigation include treatment with the plant cytokinin kinetin, which was shown to alter splicing of IKBKAP gene and significantly increase inclusion of exon 20 from the endogenous gene.