Fig. 1

Two non-related patients carrying a BVES p.V183F variant and suffering from LGMDR25. a, b Axial muscle MRI images of a patient 1 (PT1) and b patient 2 (PT2). PT1 was scanned at age 17 displaying fatty replacement and hypotrophy of the gastrocnemius medialis (arrows), with hyperintensity on T2-STIR images (arrowheads). PT2 scanned at age 50 displaying, in addition to changes in the gastrocnemius medialis (arrows), also advanced fatty replacement of adductor longus greater than in adductor magnus (arrowheads) and diffuse T2-STIR hyperintense lesions in the thigh, more evident in the anterior compartment (asterisks). c–f HE stained transverse sections of muscle biopsies taken from c PT1, e PT2 and respective matched controls d CT1 and f CT2. Note the fiber size heterogeneity in both patients. Moderately hypertrophied (arrows) and hypo/atrophied muscle fibers (asterisks) are seen. In PT1, a prominent increase in connective tissue is present. g Sequence alignment of part of the Popeye domains of vertebrate and invertebrate POPDC proteins. Color code: V183 (yellow), conserved (turquoise) and similar (green) residues. h Model of the Popeye domain of POPDC1 with the position of V183 (cyan) and the mutant V183F (pink) residues highlighted. The position of the phenylalanine side chain was determined using the Dynameomics rotamer library [41]. i The position of the V183F mutation relative to the predicted cAMP binding site as determined using the 3DLigandSite server [54]. j A model showing the possible steric clashes between the side chain of V183F (pink) with other residues of the β-folds of the Popeye domain as predicted by the Dynameomics rotamer library [41]