Myopathy With Exercise‐Induced Intolerance due to Novel Biallelic Variants in OBSCN —A Clinical, Morphological and Molecular Analysis

FIGURE 1. Skeletal muscle MRI (MR sequences: axial and coronal STIR and axial T1 FSE) of the proximal thighs of the patient showing hypertrophic muscles without oedema or fatty replacement (A). Pedigree of the family. Black symbols indicate affected probands. An arrow marks the index patient. A slash indicates deceased persons (B). Electropherograms of OBSCN sequences of the patient (C). OBSCN transcript expression was detected with two different primer pairs (covering exons 31 to 34 and exons 35 to 36) in skeletal muscle and lymphocytes. Fold change in OBSCN expression of the patient shows significantly decreased OBSCN expression compared to controls in skeletal muscle and lymphocytes; ***p < 0.001 (D). Muscle biopsy shows muscle fibres with a moderate increased variation in muscle fibre size, internalised nuclei (H&E) and predominance of type 2 fibres (MHCfast). Numerous fibres reveal central defects (arrows) with a surrounding dark rim (NADH, Gömöri, PAS) and moth‐eaten appearance in NADH (stars). Protein aggregates in the central lesions express desmin, caveolin‐3, dysferlin, autophagic marker LC3 and c5b9. Transmission electron microscopy (TEM) shows disruption of the myofibrillar…

FIGURE 2. Double immunofluorescent analysis from a control shows alternating striatal expression of desmin and obscurin at longitudinal muscle section and a stronger sarcolemmal expression of desmin compared to obscurin in cross sections. In the patient, central lesions consist of desmin aggregates with a surrounding rim of obscurin expression (arrows). Overall, the expression of obscurin is more irregular and reduced in the patient's muscle fibres (star) (B). The Volcano plot shows 69 significantly downregulated and 70 upregulated abundant proteins (DAPs) (red dots). (C) Selected gene ontology (GO) terms reveal the downregulation of pathways related to cellular respiration, mitochondrial structure and ion transmembrane transport.