Authors
Saracoglu, H. P., Nashabat, M., Kutlu, D. N., Saribas, B., Yilmaz, E., Tur, S., Kayserili, H., Yaksi, E., Nabavizadeh, N., Escande-Beillard, N.
Abstract
Loss-of-function variants in SNUPN, encoding the nuclear import factor Snurportin-1 (SPN1) required for spliceosomal small nuclear ribonucleoprotein (snRNP) transport, cause a recently described form of limb-girdle muscular dystrophy (LGMD). However, the role of SPN1 in skeletal muscle homeostasis remains poorly understood, in part due to the lack of a suitable in vivo model. Here, we generated a zebrafish snupn loss-of-function model that recapitulates key features of the skeletal muscle phenotype observed in patients. Mutant larvae developed severe locomotor impairment by 6 days post-fertilization (dpf), accompanied by sarcomeric disorganization and impaired muscle fiber integrity. Transcriptomic profiling at 6 dpf revealed widespread alternative splicing and transcriptional dysregulation, with prominent alterations in extracellular matrix and basement membrane components, together with upregulation of stress- and inflammation-associated genes. Notably, these late-stage abnormalities were preceded by disruption of the muscle progenitor population at 2 dpf, with reduced Pax7 progenitor abundance and myogenic gene expression together with altered muscle differentiation and organization. Together, these findings identify SPN1 as a key regulator of skeletal muscle homeostasis linking RNA processing to extracellular niche integrity and myogenic progenitor maintenance. This zebrafish model provides an in vivo platform for dissecting LGMD-associated disease mechanisms and developing therapeutic strategies aimed at restoring muscle function and regenerative capacity.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 01 Oct 2026.
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