SNUPN encodes Snurportin 1, a nuclear import receptor essential for transporting small nuclear ribonucleoproteins into the nucleus, which are crucial for RNA splicing. SNUPN was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2024 (Nashabat et al., PMID: 38413582). Among the 21 patients from 16 families described to date, symptom onset ranges from birth to 10 years, with progressive muscle weakness predominantly affecting proximal muscles, elevated serum creatine kinase levels, and skeletal muscle biopsies showing type I fibre predominance, hypertrophy, and fibrosis. Central nervous system involvement is variable and may include developmental delay and cerebellar atrophy. Joint contracutres, scoliosis, and ocular features like congenital bilateral cataracts may also occur, and respiratory insufficiency is common. Given the spectrum of patient phenotypes, the disease entity was defined as SNUPN-related muscular dystrophy with or without multi-system involvement.
Nine variants (4 nonsense, 2 missense, 2 frameshift, 1 splice site) reported in 21 probands from two publications (PMID: 38413582, 38366623) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence, including decreased SNUPN expression in patient fibroblasts, impaired protein-protein interaction in mutant HEK293T and HeLa cells, and aberrant RNA splicing affecting extracellular matrix components in patient fibroblasts and muscle tissue. Additionally, a muscle-specific Snup knockdown Drosophila model demonstrated age-dependent reduction in climbing activity and impaired survival (PMID: 38413582, 38366623).
In summary, there is strong evidence supporting the relationship between SNUPN and autosomal recessive SNUPN-related muscular dystrophy with or without multi-system involvement. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. Of note, SNUPN has also been implicated in spinocerebellar atrophy in a preprint (Okubo et al., MedRxiv: 2024.07.11.24310169) in 2024. This will be assessed during re-evaluation or when further evidence become available.
This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on October 8, 2024 (SOP Version 10).
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