Loss-of-function of IKAP/ELP1

Abstract

Familial dysautonomia (FD) is a hereditary neuronal disease characterized by poor development and progressive degeneration of the sensory and autonomic nervous system. Majority of FD (99.5%) results from a single nucleotide point mutation in the IKBKAP gene encoding IKAP, also known as elongation protein 1 (ELP1). The point mutation leads to variable, tissue specific expression of a truncated IKBKAP mRNA. The appearance of the truncated IKBKAP coincides with a marked reduction of its wild type mRNA leading to decreased IKAP protein levels especially in the sensory and autonomous nervous system. Recently, two independent studies were carried out to establish a cellular model system to study the loss-of-function of IKAP in mammalian cells. Both studies used RNA interference to deplete wild type IKAP from different mammalian cell types. In both studies the depletion of IKAP resulted in a cell migration defect, revealing the importance of IKAP in this process. These studies lead to a common conclusion according to which defective neuronal migration could underlie FD. They gave however two very different explanations of how IKAP would regulate cell migration: via transcriptional regulation and via cytosolic interactions.