A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions
Tekijät: 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
Kustantaja: SPRINGER
Julkaisuvuosi: 2021
Journal: Acta Neuropathologica
Lehden akronyymi: ACTA NEUROPATHOL
Vuosikerta: 142
Aloitussivu: 375
Lopetussivu: 393
Sivujen määrä: 19
ISSN: 0001-6322
eISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-021-02319-x
Verkko-osoite: https://link.springer.com/article/10.1007/s00401-021-02319-x
Rinnakkaistallenteen osoite: 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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
