RAPGEF2 – Amyotrophic Lateral Sclerosis

RAPGEF2 has been implicated in sporadic amyotrophic lateral sclerosis through the identification of a heterozygous de novo missense variant in a single early-onset patient. Using trio whole exome sequencing, a heterozygous de novo variant, c.4069G>A (p.Glu1357Lys), was discovered in one proband ([PMID:30636905]). No additional familial segregation was observed, indicating a likely autosomal dominant de novo mechanism.

Functional analyses in patient-derived fibroblasts demonstrated reduced microtubule stability, defective network morphology, impaired mitochondrial distribution, and increased recruitment of pro-apoptotic BAX. Overexpression of RAPGEF2 p.Glu1357Lys in Drosophila motor neurons recapitulated microtubule and mitochondrial trafficking defects at distal axons and neuromuscular junctions. Pharmacological inhibition of HDAC6 rescued mitochondrial distribution and BAX mislocalization, supporting a pathogenic role via microtubule dysregulation. These findings support a limited but emerging association of heterozygous de novo RAPGEF2 variants with ALS, warranting further study to establish clinical utility.

References

• Experimental neurobiology • 2018 • A De Novo RAPGEF2 Variant Identified in a Sporadic Amyotrophic Lateral Sclerosis Patient Impairs Microtubule Stability and Axonal Mitochondria Distribution. PMID:30636905

Evidence Based Scoring (AI generated)