ARHGEF28 – Amyotrophic Lateral Sclerosis

Two independent cohort studies have identified rare coding variants in the Rho guanine nucleotide exchange factor gene ARHGEF28 in sporadic amyotrophic lateral sclerosis (ALS). In a Chinese series of 399 sporadic ALS patients versus 327 elderly controls, 33 rare nonsynonymous variants (MAFT (p.Arg231Ter)) and one frameshift, suggesting a potential risk factor.

Functional studies of the RGNEF protein encoded by ARHGEF28 demonstrate misfolding, inclusion formation, and toxicity in yeast and mammalian cell models. ALS-linked truncating mutations produce aggregation-prone RGNEF that impairs the microtubule network, consistent with neuronal cytoplasmic inclusion pathology in patient tissue (PMID:32764283). These data support a toxic gain-of-function mechanism rather than haploinsufficiency.

References

• Neurobiology of aging • 2020 • Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis. PMID:31060816
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2014 • ARHGEF28 gene exon 6/intron 6 junction mutations in Chinese amyotrophic lateral sclerosis cohort. PMID:24712971
• International journal of molecular sciences • 2020 • Inclusion Formation and Toxicity of the ALS Protein RGNEF and Its Association with the Microtubule Network. PMID:32764283

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