Résumé
The 19p13.3-linked autosomal dominant myopathy is a rare distal myopathy with late onset, characterized by progressive muscle weakness and atrophy. The causative mutation affects PLIN4 gene encoding for perilipin 4, one of the most abundantly expressed perilipin proteins in the skeletal muscle tissue, where it localizes to the subsarcolemmal region of myofibers. Perilipin 4 possesses a long amphipathic (AH) region, necessary for its interaction with lipid droplets, which is organized in 31 highly similar repeats, each of them composed by 33 amino acids. A few years ago, we reported the first cases of PLIN4-related myopathy, revealing by long-read sequencing the pathological expansion of a 99 nucleotides sequence. This causes the AH region to increase from 31 to 40 repeats, resulting in 297 extra amino acids. The muscle biopsy immunostaining showed an aggregation and accumulation of the expanded perilipin 4 within the vacuoles and in the subsarcolemmal region of the myofibers. We hypothesize that with time, the removal of the protein aggregates through aggrephagy is overwhelmed and the autophagic vacuoles accumulate fusing with each other, disrupting the organization of the fibers thus impairing their contractile capacity. Recently, we identified a new sporadic case with a duplication of 14 blocks of 99 nucleotides, producing 462 extra amino acids, as confirmed by western blot analysis. Also here, the accumulation of the protein aggregates triggers the activation of the aggrephagy pathway. However, this patient presents a more proximal muscle involvement and less severe phenotype compared to the distal onset observed in the original cases. The challenging genetic screening of PLIN4, due to its repetitiveness, suggests that more patients are yet to be discovered. Moreover, the pathogenic mechanisms underlying the disease still need to be clarified.