Work

Recovery of α-L-fucosidase in fucosidosis nonsense variants by readthrough stimulation and release factor degradation

Year: 2025

Type: article

Abstract: Fucosidosis is an ultra-rare and fatal lysosomal storage disease 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 explored a therapeutic approach using translational readthrough (TR) for patients with premature termination codons 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 FUCA1 activity. Moreover, combining aminoglycoside treatment with CC-885-induced degradation of the eukaryotic release factor subunit eRF3a further enhanced FUCA1 restoration in two variants (p.Q82X and p.W188X). This study lays the groundwork for individualized TR therapy for patients with fucosidosis with FUCA1 nonsense variants.

Source: Disease Models & Mechanisms

DOI: 10.1242/dmm.052495

Authors: Hannah Bäumges, Dennis Lebeda, Philip Deppe, Mai-Britt Ilse, Sven Thoms, Torben Lübke

Institution: Bielefeld University

Language: English

Topic: Lysosomal Storage Disorders Research

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,750