Recovery of α-L-Fucosidase in Fucosidosis nonsense variants by readthrough stimulation and release factor degradation

Fucosidosis is an ultra-rare and fatal lysosomal storage disorder caused by the impaired lysosomal degradation of fucosylated glycoconjugates due to a deficiency in the lysosomal tissue α-L-fucosidase (FUCA1). The accumulation of fucosylated metabolites within lysosomes leads to a range of severe, primarily neurological, symptoms, including cognitive impairment and progressive motor dysfunction. In this study, we explore a therapeutic approach using translational readthrough (TR) for patients with premature termination codons (PTCs) resulting from nonsense mutations in the FUCA1 gene. We ectopically expressed several clinically identified FUCA1 nonsense variants in a cell line with low endogenous FUCA1 expression. Treatment with the Aminoglycoside G418 induced TR, leading to partial recovery of the full-length enzyme and α-L-fucosidase activity. Moreover, combining Aminoglycoside treatment with CC-885-induced degradation of the eukaryotic release factor subunit eRF3a further enhanced α-L-fucosidase restoration in two variants (p.Q82X and p.W188X). This study lays the groundwork for individualized TR therapy for fucosidosis patients with FUCA1 nonsense variants.

Fucosidosis; Nonsense mutations; Premature termination codons; Translational Readthrough; α-L-fucosidase.