ABSTRACT
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.
Subject(s)
Alveolitis, Extrinsic Allergic , Ubiquitin-Activating Enzymes , Humans , Male , Aged , Alveolitis, Extrinsic Allergic/genetics , Alveolitis, Extrinsic Allergic/diagnosis , Ubiquitin-Activating Enzymes/genetics , Syndrome , Vacuoles , Diagnosis, Differential , Tomography, X-Ray Computed , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/diagnosis , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/complications , Mutation , Lung Diseases, Interstitial/genetics , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/diagnostic imaging , Lung/diagnostic imaging , Lung/pathologyABSTRACT
Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.
Subject(s)
Autophagy-Related Protein-1 Homolog/metabolism , Autophagy , Ubiquitin-Protein Ligases/genetics , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line , Cell Transdifferentiation , Humans , Lysine/metabolism , Mice , Mice, Knockout , Muscular Dystrophies, Limb-Girdle/metabolism , Muscular Dystrophies, Limb-Girdle/pathology , Myoblasts/cytology , Myoblasts/metabolism , Protein Binding , RNA Interference , RNA, Small Interfering/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
Authors have measured interorbital radiological distance in 45 newborns (26 males and 19 females), with a gestational age of 37.644 +/- 3.682 weeks (mean +/- SD), with a range of 25 to 42 weeks. The values obtained were 15.538 +/- 2.437 millimeters (mean +/- SD) for males and 15.894 +/- 1.943 mm (mean +/- SD) for females. The interorbital distance has a positive correlation with gestational age, weight, bizygomatic distance and minimal frontal width. Interorbital distance is closely correlated to the minimal frontal width in males.
