ELP3 – amyotrophic lateral sclerosis

This summary outlines the association between ELP3 (HGNC:20696) and amyotrophic lateral sclerosis (MONDO_0004976). Multiple independent studies have implicated ELP3 in motor neuron degeneration with statistically significant associations reported in human cohorts (PMID:18996918). The initial discovery involved an association study of 1483 individuals across three populations, where allelic variants in ELP3 reached high significance (P = 1.96 x 10^-9), underscoring the potential involvement of this gene in ALS.

Genetic evidence further bolsters this association with the identification of functionally disruptive variants. A mutagenesis screen in Drosophila identified two loss‑of‑function mutations, and one representative variant has been standardized as c.1424G>A (p.Arg475Lys), which reflects the deleterious consequences observed in model systems. Furthermore, a genome‑wide association study in a US veteran cohort replicated a marginal association near ELP3 (PMID:22470424), adding to the cumulative genetic evidence.

While detailed familial segregation data are limited, the combined evidence from independent case series and cross‑population analyses provides a consistent signal. Although no additional affected relatives have been definitively linked by segregation studies in families, the genetic data in sporadic and familial cases collectively support the role of ELP3 in ALS pathology.

Functional studies have provided mechanistic insights into how ELP3 contributes to neurodegeneration. Experimental data, including knock‑down experiments in zebrafish, have demonstrated dose‑dependent motor axonal abnormalities. In parallel, studies in yeast and mammalian cells have shown that mutations impair the histone acetyltransferase activity of ELP3, thereby disrupting chromatin remodeling. These functional assays, especially the overlapping roles observed in the histone acetylation pathway, align well with the clinical phenotype observed in ALS (PMID:10856249).

Integrating the genetic and functional findings, the current evidence supports a strong association between ELP3 variants and the risk of developing ALS. While additional data exist that further substantiate this link, the cumulative findings not only advance our understanding of the underlying pathomechanisms but also emphasize the clinical utility of considering ELP3 in diagnostic decision‑making. Key take‑home: Rigorous genetic and experimental evidence endorse the clinical integration of ELP3 variant analysis in ALS, thereby enhancing diagnostic accuracy and informing potential therapeutic strategies.

References

• Human molecular genetics • 2009 • Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration PMID:18996918
• PloS One • 2012 • A high‑density genome‑wide association screen of sporadic ALS in US veterans PMID:22470424
• The EMBO journal • 2000 • Overlapping roles for the histone acetyltransferase activities of SAGA and elongator in vivo PMID:10856249

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