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SNUPN-Related Muscular Dystrophy: Novel Phenotypic, Pathological and Functional Protein Insights
Nuria Muelas1,2,3,4, Pablo Iruzubieta5,6,7, Alberto Damborenea5
1Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Annals of Clinical and Translational Neurology
|October 7, 2025
Summary
This study identifies adult-onset SNUPN-related muscular dystrophy (LGMDR29) with novel genetic variants and ultrastructural findings. The research expands understanding of this rare muscular dystrophy and its pathological mechanisms.
Area of Science:
- Neurology
- Genetics
- Cell Biology
Background:
- SNUPN-related muscular dystrophy (LGMDR29) is a rare disorder with variable onset and phenotypes.
- Previously, 12 variants in the SNUPN gene were identified, associated with congenital or childhood-onset muscular dystrophy, sometimes with neurodevelopmental features, cataracts, or ataxia.
Purpose of the Study:
- To report the first family with SNUPN-related muscular dystrophy presenting with adult-onset myopathy.
- To describe novel ultrastructural findings in muscle tissue.
- To elucidate the functional consequences of identified SNUPN variants.
Main Methods:
- Clinical evaluation, muscle and brain MRI, and histopathological analysis including electron microscopy.
- Functional studies encompassing protein modeling, immunofluorescence, and splicing analysis.
Main Results:
- Two siblings with novel SNUPN variants (p.Arg27Cys, p.Cys174Tyr) exhibited adult-onset proximo-distal and axial muscle weakness with early respiratory involvement.
- Histopathology revealed dystrophic changes, abnormal cytoskeletal/myofibrillar proteins, and electron microscopy showed granular deposits and membrane remodeling.
- Functional studies indicated impaired snurportin-1 function, affecting nuclear import of small nuclear ribonucleoproteins and downstream splicing.
Conclusions:
- This study expands the clinical and pathological spectrum of SNUPN-related muscular dystrophy (LGMDR29) to include adult-onset myopathy.
- Novel granular deposits suggest perturbed cellular traffic and homeostasis, offering insights into disease mechanisms.
- SNUPN gene testing is recommended for patients with late-onset myopathy, respiratory impairment, and IBM-like features.
