Collagen VI is an extracellular matrix component encoded by COL6A1, COL6A2 and COL6A3 genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We report the mutation landscape of COL6A genes in 138 Italian patients affected with a collagen VI-related phenotype. The patient cohort included 44 (32%) UCMD, 9 (7%) INT, 61 (44%) BM and 21 (15%) INT/BM patients; 3 patients (2%) with a myosclerosis myopathy (MM) phenotype were also considered. We identified 104 different variants: 26 in COL6A1 (25%), 52 in COL6A2 (50%) and 26 in COL6A3 (25%). The variant spectrum includes missense, splicing, small indel, frameshifting and nonsense variants. Glycine substitutions in the triple helical domain of the collagen VI protein are the commonest variants and occur in all phenotypes. Our genetic profiling disclosed a unique mutation scenario and phenotypic association of the COL6A2 gene with respect to COL6A1 and COL6A3, which may be related to a different evolutive history. Landscape mutation analysis of variants occurring in ultrarare conditions, such as collagen VI-related myopathies, is crucial to better understand the variations' profile and to gain insight into fundamental knowledge about gene structure and its evolutive origin.

Aromatase inhibitors (AIs) are commonly used to treat postmenopausal hormone receptor positive breast cancer, but there is currently a lack of comprehensive safety reports on AIs in large-scale cohorts. We conducted a retrospective pharmacovigilance survey based on the FDA Adverse Event Reporting System, retrieving relevant reports from the 2004 to the 2023, aiming to conduct a comprehensive comparative analysis of adverse reactions associated with AIs. In addition, we elucidated the potential toxicological mechanisms of AIs related adverse events through functional enrichment analysis. A total of 7,933 adverse event reports related to AIs were collected, and there were 642 positive signals at the preferred term level. The top three signal intensities for anastrozole are: antiphospholipid syndrome, plantar fasciitis and autoimmune pancreatitis. The top three signal intensities for letrozole are: androgenetic alopecia and myosclerosis, pneumonic herpes virus. The top three signal intensities for exemestane are: infection reactivation, thyroxine free decreased and dilatation atrial. In terms of onset time, letrozole has the earliest onset time overall, followed by exemestane, and finally anastrozole. Our research corroborates the typical adverse events linked to AIs while highlighting potential safety concerns in their real-world clinical application.

Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.

Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, COL6A1, COL6A2 and COL6A3, are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients' derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies.

Mutations in the genes encoding collagen VI cause Bethlem myopathy (MIM 158810), Ullrich congenital muscular dystrophy (MIM 254090), and myosclerosis myopathy (MIM #255600). BM is a dominantly inherited disorder, characterised by proximal muscle weakness and joint contractures mainly involving the elbows, ankles, and fingers, which usually follows a relatively mild course. By contrast, UCMD is a severe muscular dystrophy characterized by early onset, rapidly progressive muscle wasting and weakness, proximal joint contractures and distal joint hyperlaxity. Rapid progression usually leads to early death due to respiratory failure. UCMD is usually inherited as an autosomal recessive trait though dominant de novo heterozygous variants have recently been reported. We describe a further patient with UCMD classical presentation who showed, at the NGS analysis, the de novo variant c.6210+1G > A in the intron 16 of the gene COL6A3, known in the literature as pathogenic (VCV0000949S6.5).