ELP1 Gene

The ELP1 gene (ELP1 is the acronym for Elongator Complex Subunit 1) also referred to as the IKBKAP gene, is a protein-coding gene located on chromosome 9q3. 1 The gene encodes the ELP1 protein, a subunit of the RNA polymerase 2 elongator complex, which consists of ELP1, STIP1/ELP2, ELP3, ELP4, ELP5, and ELP6. Mutations in the ELP1 gene cause degeneration of sensory sympathetic (and in some cases parasympathetic) nerves.

Diseases associated with ELP1 include Riley-Day syndrome. Associated pathways include transcription, the NF-kappa B pathway , and chromatin regulation/acetylation (Cheishvili D et al. 2011; Naumanen Tet al. 2008).

The ELP1 protein is the largest subunit of the evolutionarily conserved Elongator complex, which catalyzes translational elongation through tRNA modifications at the wobble position (U34). Tumors from patients with ELP1-associated MBSHH are characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the "unfolded protein response," consistent with loss of protein homeostasis due to Elongator deficiency in model systems.

The Elongator complex catalyzes the formation of carboxymethyluridine at the "wobble base " in position 34 in tRNAs . It is involved in neurogenesis. Regulates migration and branching of projection neurons in the developing cerebral cortex through a process dependent on alpha-tubulin acetylation. May function as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB, and MAP3K14/NIK) (Waszak SM et al. 2020).

With the rapid development of cryo-electron microscopy (cryo-EM), several near-atomic structures of such higher-order transcriptional complexes of Pol II have recently been described, especially those involved in transcription initiation.

Pathogenic germline variants in established cancer predisposition genes were recently identified in 5% of patients with the malignant brain tumor medulloblastoma (Waszak SM et al. 2020).

In the medulloblastoma subgroup Sonic Hedgehog (MBSHH), rare germline variants with loss of function in ELP1 can be detected in 14% of cases. The ELP1 gene is the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% in pediatric patients with MBSHH. Most ELP1-associated medulloblastomas also had somatic alterations in PTCH1, suggesting that germline ELP1 loss-of-function variants combined with constitutive activation of the SHH pathway predispose to tumor development.

1. Cheishvili D et al. (2011) IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia. Hum Mol Genet 20:1585-1594.
2. Naumanen Tet al. (2008) Loss-of-function of IKAP/ELP1: could neuronal migration defect underlie familial dysautonomia? Cell Adh Migr 2: 236-239.
3. Waszak SM et al (2020) Germline Elongator mutations in sonic hedgehog medulloblastoma. Nature 580: 396-401.