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.

Retina-specific loss ofIkbkap/Elp1causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia

“…Why neurons die in the absence of IKAP is not fully resolved, nor have we thoroughly identified its function(s) in neurons. In other systems, loss of IKAP also impairs target innervation, exocytosis, cytoskeletal organization and axonal transport, which might directly and/or indirectly lead to cell death ( Abashidze et al, 2014 ; Chaverra et al, 2017 ; Close et al, 2006 ; George et al, 2013 ; Hunnicutt et al, 2012 ; Jackson et al, 2014 ; Johansen et al, 2008 ; Lefler et al, 2015 ; Naftelberg et al, 2016 ; Naumanen et al, 2008 ; Tourtellotte, 2016 ). IKAP/ELP1 is the scaffolding subunit of the six-subunit elongator complex, which is required for the translation of codon-biased genes.…”

“…In its absence, translation of codon-biased mRNAs is impaired, resulting in perturbations in levels of specific proteins ( Goffena et al, 2018 ). Either as a direct or indirect consequence of this altered translation, Ikbkap conditional knockout (CKO) neurons exhibit impaired axonal transport, target innervation and cell survival ( Abashidze et al, 2014 ; Chaverra et al, 2017 ; Close et al, 2006 ; George et al, 2013 ; Hunnicutt et al, 2012 ; Jackson et al, 2014 ; Johansen et al, 2008 ; Lefler et al, 2015 ; Naftelberg et al, 2016 ; Naumanen et al, 2008 ; Tourtellotte, 2016 ; Ueki et al, 2016 ).…”

The Genetic Landscape of a Cell

“…These findings suggest that Elp and Urm pathways may be biased toward the regulation of a functionally specific subset of cellular proteins. ELP1 is a highly conserved gene whose human ortholog, inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex–associated protein (IKBKAP), is associated with a neurological disorder, familial dysautonomia, which leads to disruption of cytoskeletal organization when mutated (18, 19). Thus, it is possible that disease manifestation may involve impaired IKBKAP-dependent translation of a set of human genes belonging to a specific functional group.…”

Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

“…Mutations in the donor splice site of intron 20 of ELP1/IKBKAP gene (an Elongator complex subunit) have been linked to familial dysautonomia (FD) (Figure 3; Table 1), a hereditary genetic disorder characterized by improper development and function of the sensorial and autonomic nerve systems [66]. In fact, most cases of FD (99.5%) result from a single nucleotide point mutation in the IKBKAP gene [67], and brain tissue as well as fibroblast cell lines from FD patients have reduced levels of mcm 5 s 2 U modification [68]. Hypomodification of the wobble uridine of tRNAs for Val, Gly, Thr, and Arg of FD patient cells was reverted after rectifying the aberrant splicing of IKBKAP pre-mRNAs harboring an FD-causing mutation [69].…”