A1 Refereed original research article in a scientific journal
Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions
Authors: Johari Mridul, Sarparanta Jaakko, Vihola Anna, Jonson Per Harald, Savarese Marco, Jokela Manu, Torella Annalaura, Piluso Giulio, Said Edith, Vella Nrbert, Cauchi Marija, Magot Armelle, Magri Francesca, Mauri Eleonora, Kornblum Cornelia, Reimann Jens, Stojkovic Tanya, Romero Norma B., Luque Helena, Huovinen Sanna, Lahermo Päivi, Donner Kati, Comi Giacomo Pietro, Nigro Vincenzo, Hackman Peter, Udd Bjarne
Publisher: SPRINGER
Publication year: 2021
Journal: Acta Neuropathologica
Journal acronym: ACTA NEUROPATHOL
Volume: 142
First page : 375
Last page: 393
Number of pages: 19
ISSN: 0001-6322
eISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-021-02319-x
Web address : https://link.springer.com/article/10.1007/s00401-021-02319-x
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/58940372
Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.
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