Distal myopathies are genetically heterogeneous diseases that primarily affect skeletal muscles, particularly in the hands and feet, although they can progress to other muscles. Previous research has identified more than 25 genes associated with these conditions, but many patients still remain undiagnosed. SMPX (small muscle protein X-linked), a gene involved in muscle function, has previously been associated with non-muscle-related conditions such as hearing loss, but a study from Folkhälsan Research Center in Finland reveals its role in distal myopathy with protein inclusions.
The study, published in Acta Neuropathologica performed deep phenotyping and genetic sequencing on 10 patients from 9 families, revealing 4 distinct SMPX mutations, which cause progressive distal myopathy. By taking muscle biopsies and staining them with Amytracker 680, they confirmed that some of the sarcoplasmic inclusions present in the muscle fibres had amyloid-like characteristics. Moreover, cell culture experiments showed that these mutations increase protein aggregation and slow down the clearance of stress granules.
The study concludes that missense mutations in SMPX lead to a previously unknown form of distal myopathy, hallmarked by inclusion bodies in the muscles. These sarcoplasmic inclusions have amyloid-like characteristics - as highlighted by Amytracker staining - and represent a novel disease mechanism distinct from the hearing loss caused by other SMPX mutations.
Image: Amyloid-like protein inclusions of SMPX in muscle tissue stained with Amytracker 680 (magenta) and SMPX and myotilin (green). Absence of Amytracker staining in the control (ctrl) sample confirms lack of autofluorescence from protein inclusions. Image from Figure 5B, Johari et al. (2021) Acta Neuropathologica, 142, 375-393 (CC BY 4.0).