Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
- Creators
- Donkervoort S.
- Kutzner C. E.
- Hu Y.
- Lornage X.
- Rendu J.
- Stojkovic T.
- Baets J.
- Neuhaus S. B.
- Tanboon J.
- Maroofian R.
- Bolduc V.
- Mroczek M.
- Conijn S.
- Kuntz N. L.
- Topf A.
- Monges S.
- Lubieniecki F.
- McCarty R. M.
- Chao K. R.
- Governali S.
- Bohm J.
- Boonyapisit K.
- Malfatti E.
- Sangruchi T.
- Horkayne-Szakaly I.
- Hedberg-Oldfors C.
- Efthymiou S.
- Noguchi S.
- Djeddi S.
- Iida A.
- di Rosa G.
- Fiorillo C.
- Salpietro V.
- Darin N.
- Faure J.
- Houlden H.
- Oldfors A.
- Nishino I.
- de Ridder W.
- Straub V.
- Pokrzywa W.
- Laporte J.
- Foley A. R.
- Romero N. B.
- Ottenheijm C.
- Hoppe T.
- Bonnemann C. G.
- Others:
- Donkervoort, S.
- Kutzner, C. E.
- Hu, Y.
- Lornage, X.
- Rendu, J.
- Stojkovic, T.
- Baets, J.
- Neuhaus, S. B.
- Tanboon, J.
- Maroofian, R.
- Bolduc, V.
- Mroczek, M.
- Conijn, S.
- Kuntz, N. L.
- Topf, A.
- Monges, S.
- Lubieniecki, F.
- Mccarty, R. M.
- Chao, K. R.
- Governali, S.
- Bohm, J.
- Boonyapisit, K.
- Malfatti, E.
- Sangruchi, T.
- Horkayne-Szakaly, I.
- Hedberg-Oldfors, C.
- Efthymiou, S.
- Noguchi, S.
- Djeddi, S.
- Iida, A.
- di Rosa, G.
- Fiorillo, C.
- Salpietro, V.
- Darin, N.
- Faure, J.
- Houlden, H.
- Oldfors, A.
- Nishino, I.
- de Ridder, W.
- Straub, V.
- Pokrzywa, W.
- Laporte, J.
- Foley, A. R.
- Romero, N. B.
- Ottenheijm, C.
- Hoppe, T.
- Bonnemann, C. G.
Description
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.
Additional details
- URL
- http://hdl.handle.net/11567/1065231
- URN
- urn:oai:iris.unige.it:11567/1065231
- Origin repository
- UNIGE