Search

Aims: Diagnosis of idiopathic inflammatory myopathies (IIM) is based on morphological characteristics and the evaluation of disease‐related proteins. However, although broadly applied, substantial bias is imposed by the respective methods, observers and individual staining approaches. We aimed to quantify the protein levels of major histocompatibility complex (MHC)‐1, (MHC)‐2 and intercellular adhesion molecule (ICAM)‐1 using an automated morphometric method to mitigate bias. Methods: Double immunofluorescence staining was performed on whole muscle sections to study differences in protein expression in myofibre and endomysial vessels. We analysed all IIM subtypes including dermatomyositis (DM), anti‐synthetase syndrome (ASyS), inclusion body myositis (IBM), immune‐mediated‐necrotising myopathy (IMNM), dysferlinopathy (DYSF), SARS‐CoV‐2 infection and vaccination‐associated myopathy. Biopsies with neurogenic atrophy (NA) and normal morphology served as controls. Bulk RNA‐Sequencing (RNA‐Seq) was performed on a subset of samples. Results: Our study highlights the significance of MHC‐1, MHC‐2 and ICAM‐1 in diagnosing IIM subtypes and reveals distinct immunological profiles. RNASeq confirmed the precision of our method and identified specific gene pathways in the disease subtypes. Notably, ASyS, DM and SARS‐CoV‐2‐associated myopathy showed increased ICAM‐1 expression in the endomysial capillaries, indicating ICAM‐1‐associated vascular activation in these conditions. In addition, ICAM‐1 showed high discrimination between different subgroups with high sensitivity and specificity. Conclusions: Automated morphometric analysis provides precise quantitative data on immune‐associated proteins that can be integrated into our pathophysiological understanding of IIM. Further, ICAM‐1 holds diagnostic value for the detection of IIM pathology. [ABSTRACT FROM AUTHOR]

This article explores the distribution and composition of the ferritin complex in the adult brain and its connection to neuroferritinopathy (NF), a type of neurodegeneration with brain iron accumulation (NBIA). NF is characterized by symptoms like movement disturbances and tremors. The study identifies a novel variant in the ferritin heavy chain gene (FTH1) that is associated with NF and provides insights into the role of ferritin in both healthy and diseased brains. [Extracted from the article]

Popeye domain containing protein 1 (POPDC1) is a highly conserved transmembrane protein essential for striated muscle function and homeostasis. Pathogenic variants in the gene encoding POPDC1 (BVES, Blood vessel epicardial substance) are causative for limb-girdle muscular dystrophy (LGMDR25), associated with cardiac arrhythmia. We report on four affected children (age 7–19 years) from two consanguineous families with two novel pathogenic variants in BVES c.457C>T(p.Q153X) and c.578T>G (p.I193S). Detailed analyses were performed on muscle biopsies from an affected patient of each family including immunofluorescence, electron microscopy and proteomic profiling. Cardiac abnormalities were present in all patients and serum creatine kinase (CK) values were variably elevated despite lack of overt muscle weakness. Detailed histological analysis of skeletal muscle, however indicated a myopathy with reduced sarcolemmal expression of POPDC1 accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1 abundance. At the electron microscopic level, the muscle fiber membrane was focally disrupted. The proteomic signature showed statistically significant dysregulation of 191 proteins of which 173 were increased and 18 were decreased. Gene ontology-term analysis of affected biological processes revealed - among others - perturbation of muscle fibril assembly, myofilament sliding, and contraction as well as transition between fast and slow fibers. In conclusion, these findings demonstrate that the phenotype of LGMDR25 is highly variable and also includes younger children with conduction abnormalities, no apparent muscular problems, and only mildly elevated CK values. Biochemical studies suggest that BVES mutations causing loss of functional POPDC1 can impede striated muscle function by several mechanisms. • Two novel mutations in BVES are associated with an early onset of LGMD25. • Loss of POPDC1 is accompanied by altered sarcolemmal and sarcoplasmatic dysferlin and Xin/XIRP1. • In children with cardiac symptoms, a neuromuscular disorder should be ruled out. • Expression of POPDC1 in cardiac muscle highlights the cardio-skeletal link in LGMD. [ABSTRACT FROM AUTHOR]