NEW GENES IN NEUROMUSCULAR DISEASES

Distal myopathies are a clinically, histopathologically and genetically heterogeneous group of inherited skeletal muscle diseases with muscle weakness predominantly observed in the distal muscles. Despite advancements in high throughput sequencing, a number of patients remain without a molecular diagnosis. Especially sporadic distal myopathy cases, often due to lack of additional family history, usually cannot progress beyond candidate gene approaches. Taking advantage of deep phenotyping and histopathological evidence, we have identified the small muscle protein X gene (SMPX) as a novel disease gene causing the first X-linked form of distal myopathy. Using exome and targeted panel sequencing, we detected mutations in six unrelated sporadic male patients with an adult-onset, distal muscle weakness, usually both in lower and upper limbs, sharing common clinical and histopathological findings. We report four different missense variants, including two founder haplotypes in the Italian population and Northern French populations, strongly suggesting the underestimation of this disease in Mediterranean countries. Additionally, we have identified two different missense changes in a German and a Finnish patient. Functional evidence in HeLa and C2C12 cells suggest that the mutant proteins behave differently than the wild type SMPX by affecting the formation of lamellipodia. We are currently investigating the effect of these mutations in zebrafish models.