Variants of the elongator protein 3 ( ELP3 ) gene are associated with motor neuron degeneration

TLDR

Amyotrophic lateral sclerosis is a relentlessly progressive motor neuron disease that typically leads to death within three years, and while mutations in SOD1 and TARDBP explain only a small fraction of cases, the majority of genetic causes remain unknown. Genome‑wide association and Drosophila mutagenesis screens identified ELP3 allelic variants and loss‑of‑function mutations that are strongly associated with ALS. Loss of ELP3 function in zebrafish leads to motor axonal defects, and risk‑associated human ELP3 variants are linked to lower brain expression, supporting a key role for ELP3 in neuronal biology and ALS pathogenesis.

Abstract

Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3 , in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people ( P = 1.96 × 10 −9 ). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: −0.49, P = 1.83 × 10 −12 (start codon morpholino) and −0.46, P = 4.05 × 10 −9 (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression ( P = 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS.