Elongator and the role of its subcomplexes in human diseases.

The Elongator complex was initially identified in yeast, and a variety of distinct cellular functions have been assigned to the complex. In the last decade, several research groups focussed on dissecting its structure, tRNA modification activity and role in translation regulation. Recently, Elongator emerged as a crucial factor for various human diseases, and its involvement has triggered a strong interest in the complex from numerous clinical groups. The Elongator complex is highly conserved among eukaryotes, with all six subunits (Elp1-6) contributing to its stability and function. Yet, recent studies have shown that the two subcomplexes, namely the catalytic Elp123 and accessory Elp456, may have distinct roles in the development of different neuronal subtypes. This Commentary aims to provide a brief overview and new perspectives for more systematic efforts to explore the functions of the Elongator in health and disease.

Functional divergence of the two Elongator subcomplexes during neurodevelopment.

The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.

The Correlation of ELP4-PAX6 With Rolandic Spike Sources in Idiopathic Rolandic Epilepsy Syndromes.

Objective: To study the single nucleotide polymorphism rs662702 of ELP4-PAX6 in patients with idiopathic rolandic epilepsy syndromes (IRES) in China and explore the relationship between the distribution of rolandic spike sources and the single nucleotide polymorphism rs662702 in ELP4-PAX6. Methods: First, clinical information was obtained from patients diagnosed with IRES. Next, the single nucleotide polymorphism rs662702 of ELP4 was analyzed by using the Sanger method. Resting-state magnetoencephalography data were collected from 17 patients. We analyzed the epileptic spike sources using the single equivalent current dipole (SECD) model and determined the spike distributions across the whole brain. Finally, Fisher's test was performed to assess the correlation between the single nucleotide polymorphism rs662702 of ELP4-PAX6 and rolandic spike sources. Results: ELP4 rs662702 T alleles were found in 10.7% of IRES patients and occurred four times more frequently in these patients than in the healthy controls. TT homozygosity was found in one IRES patient (1.3%), while no TT homozygosity was found in the healthy control group. The IRES rolandic spike sources were unilateral in sixteen patients (94.1%) and were mainly located in the anterior central gyrus (58.8%). The spike source of patients without the ELP4 rs662702 T allele was correlated with the central region (p < 0.05). The rolandic spikes sources were significant correlated with the non-central gyrus (frontal and temporal lobes) in patients with the ELP4 rs662702 T allele (p < 0.05). Conclusion: The rolandic spike sources of the IRES patients with the ELP4 rs662702 T allele were significantly associated with the non-central gyrus, including the frontal and temporal lobes. Our study confirmed for the first time in vivo that ELP4 rs662702 T allele overexpression is correlated with the rolandic spike distribution in patients with IRES and provides important insights into how genetic abnormalities can lead to brain dysfunction and into the precise targeting of abnormal discharge sources in the brain.

Association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst.

OBJECTIVE: The association between ELP4 rs986527 polymorphism and the occurrence and development of intracranial arachnoid cyst was studied in this paper. METHODS: Eighty-five patients diagnosed with intracranial arachnoid cysts by cerebral computed tomography scan were selected. Sixty-three healthy volunteers for medical examination in hospitals served as controls. The cognition, depressive symptoms, and the likelihood of headache, dizziness, head trauma history, dementia, depression, and epilepsy were assessed. ELP4 genotypes and its allele frequency were determined by PCR, endonuclease restriction analysis, and gel electrophoresis. RESULTS: ELP4 rs986527 had three genotypes: TT, TC, and CC. The intracranial arachnoid cyst group showed no statistically significant difference in genotype frequencies compared with healthy controls. There was no significant correlation between ELP4 rs986527 polymorphism and location of intracranial arachnoid cyst. TC and C genotype frequencies were associated with a higher incidence of clinical symptoms than TT genotype frequencies, and C allele frequencies were associated with a significantly higher incidence of clinical symptoms compared with T allele frequencies. There was no significant difference in TNF-α and IL-1ß levels between TT/TC/CC genotypes before treatment. After treatment, the levels of TNF-α and IL-1ß were significantly decreased in different genotypes, and the decrease in CC was the greatest. The frequency of TT and TC genotypes was higher than that of CC genotypes. CONCLUSION: ELP4 rs986527 polymorphism affected the incidence of clinical symptoms and the levels of TNF-α and IL-1ß in patients with intracranial arachnoid cysts.

Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.

The Elongator is a complex with multiple subunits (Elp1-Elp6) which promotes transcript elongation and protein translation. In this study, we investigated the effects of Elongator on the migration and invasion of HCC cells as well as the underlying mechanisms. We showed that overexpression of Elp3 or Elp4 promoted the migration and invasion of HCC cells, which was abolished when either Elp3 or Elp4 was silenced. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 were enhanced by phosphorylation of AKT. Elongator-driven migration and invasion and the expression of MMP-2 and MMP-9 were reduced in HCC cells treated with AKT inhibitor LY294002. Depletion of Elp3 also reduced the phosphorylation of AKT induced by growth factors. In vivo assay of lung metastasis in mice demonstrated that overexpression of Elp3 increased tumor nodules metastatic to lung. Importantly, Elp3 was up-regulated in human HCC tissues, which was correlated with the phosphorylation of AKT and expression of MMP-2. Collectively, these results suggested that Elongator activated migration and invasion of HCC cells by promoting the expression of MMP-2 and MMP-9 through the PI3K/AKT signaling pathway. Our work suggests that Elongator might be a potential marker which promotes the metastasis of HCC.

Association of brain-derived neurotrophic factor (BDNF) and elongator protein complex 4 (ELP4) polymorphisms with benign epilepsy with centrotemporal spikes in a Greek population.

PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common childhood epileptic syndrome. Different mutations in genes that control the excitability of neurons have been described. Recent reports on the involvement of the BDNF and ELP4 genes in cell motility, migration, and adhesion raise the possibility that these genes are involved in pathogenesis of BECTS. MATERIALS AND METHODS: We conducted a case-control association study on 60 patients with BECTS and 60 control participants to assess the influence of the BDNF and ELP4 polymorphisms on BECTS. The polymorphisms were detected with a PCR-RFLP method. Moreover, we explored the possible association of these polymorphisms with clinical and electroencephalographic parameters of patients with BECTS. RESULTS: Our results show no difference in BDNF and ELP4 genotype frequencies between patients and controls. Haplotype analysis also revealed no statistical difference. CONCLUSION: The role of BDNF and ELP4 polymorphisms remains controversial.

Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective on why progress on identifying genetic influences on common epilepsies has been so slow.

In this chapter, we will use the concepts and perspective of population genetics and genetic analysis to discuss the trends that are currently popular in the epilepsy genetics literature. We will also show that some of the recent approaches to understanding epilepsy genetics are unlikely to lead to insight into the causes of the most common epilepsies. Much effort has been directed toward very rare influences on epilepsy expression and away from approaches that could shed light on the most heritable epilepsies. The latest genetic technology, e.g., exome sequencing and copy number variants (CNV) analysis, has been applied without proper consideration of the important principles of population genetics, inheritance, or phenotype definition that are critical in common disease studies. We will show that ignoring these issues has led to unlikely suppositions about etiology and about which genes should be pursued. We also suggest that, taken together, the existing evidence supports a neurodevelopmental origin for common epilepsies. We recommend a return to thorough phenotype definition and family studies and a more careful and thoughtful application of the new technology.