Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

Abstract

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

Maintaining proteostasis under mechanical stress

“…On the other hand, UNC‐45B is predominantly expressed in striated muscles. Indeed, abnormal UNC‐45B function is associated with severe muscle defects resulting in skeletal and cardiac myopathies (Janiesch et al , 2007 ; Donkervoort et al , 2020 ).…”

“…It thus provides a multisite‐docking platform to assemble myosin filaments in a precisely defined pattern into thick myofilaments and eventually myofibrils (Fig 2E ). Importantly, this highly conserved chaperone system is required not only for sarcomere formation during development but also for its maintenance in the contracting muscle (Kim et al , 2008 ; Gaiser et al , 2011 ; Pokrzywa & Hoppe, 2013 ; Donkervoort et al , 2020 ). In response to stress or damage to the myofibre, HSP90 and UNC‐45 dissociate from the Z‐disc and transiently associate with myosin (Etard et al , 2008 ), indicating their essential involvement in assembly processes under mechanical stress.…”

“…The inactivation or deregulation of mechanical stress protection factors causes severe pathology in humans. For example, mutations in BAG3 give rise to skeletal muscle myopathies and cardiomyopathies (Claeys et al , 2013 ; Fang et al , 2017 ; Kimura et al , 2021 ), a decline of BAG3 activity contributes to heart failure (Martin et al , 2021 ), and mutation‐induced functional impairment of UNC‐45 leads to skeletal muscle myopathy and ovarian and breast cancer (Bazzaro et al , 2007 ; Janiesch et al , 2007 ; Donkervoort et al , 2020 ). Advancing our knowledge about mechanical stress protection systems in humans will thus be instrumental for the diagnosis of diverse diseases and may pave the road for therapeutic intervention using, for example, proteostasis modulators, such as the autophagy inducing compound rapamycin.…”

“…An extensive body of work has elucidated the adaptation of cellular folding and degradation machineries in response to heat, oxidative and proteotoxic stress (Richter et al , 2010 ; Vihervaara & Sistonen, 2014 ; Dahl et al , 2015 ; Sala et al , 2017 ; Nillegoda et al , 2018 ; Dahiya & Buchner, 2019 ; Hipp et al , 2019 ; Rosenzweig et al , 2019 ). In contrast, the impact of mechanical stress on these machineries became only recently apparent, when force‐regulated proteostasis systems were identified and shown to be essential for cell and tissue homeostasis (Janiesch et al , 2007 ; Arndt et al , 2010 ; Gazda et al , 2013 ; Ulbricht et al , 2013 , 2015 ; Kathage et al , 2017 ; Rinschen et al , 2017b ; Donkervoort et al , 2020 ).…”

Genome-Wide Analysis Reveals Selection Signatures Involved in Meat Traits and Local Adaptation in Semi-Feral Maremmana Cattle

“…The protein encoded by this gene appears to cross-link microtubules and microfilaments in muscle ( Stroud et al, 2014 ). UNC45B is essential for sarcomeric organization and muscle function in very distinct taxonomic groups spanning from Caenorhabditis elegans to humans ( Donkervoort et al, 2020 ) and is among a group of genes that showed statistically significant differences in their expression between beef and dairy cattle ( Ciecierska et al, 2020 ). Therefore, our findings partially reflect the different breeding schemes for meat quality traits between Maremmana and the other Podolian-derived Italian breeds.…”