Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
Sandra Donkervoort
(1)
,
Carl E. Kutzner
(2)
,
Ying Hu
(1)
,
Xavière Lornage
(3)
,
John Rendu
(4, 5)
,
Tanya Stojkovic
(6)
,
Jonathan Baets
(7)
,
Sarah B. Neuhaus
(1)
,
Jantima Tanboon
(8)
,
Reza Maroofian
(9)
,
Véronique Bolduc
(1)
,
Magdalena Mroczek
(10)
,
Stefan Conijn
(11)
,
Nancy L. Kuntz
(12)
,
Ana Töpf
(10)
,
Soledad Monges
(13)
,
Fabiana Lubieniecki
(13)
,
Riley M. Mccarty
(1)
,
Katherine R. Chao
(14)
,
Serena Governali
(11)
,
Johann Böhm
(3)
,
Kanokwan Boonyapisit
(8)
,
Edoardo Malfatti
(15)
,
Tumtip Sangruchi
(8)
,
Iren Horkayne-Szakaly
(16)
,
Carola Hedberg-Oldfors
(17)
,
Stephanie Efthymiou
(9)
,
Satoru Noguchi
(18)
,
Sarah Djeddi
(3)
,
Aritoshi Iida
(18)
,
Gabriella Di Rosa
(19)
,
Chiara Fiorillo
(20)
,
Vincenzo Salpietro
(20)
,
Niklas Darin
(17)
,
Julien Fauré
(4, 5)
,
Henry Houlden
(9)
,
Anders Oldfors
(17)
,
Ichizo Nishino
(18)
,
Willem de Ridder
(7)
,
Volker Straub
(10)
,
Wojciech Pokrzywa
(21)
,
Jocelyn Laporte
(3)
,
A. Reghan Foley
(1)
,
Norma B. Romero
(6, 22)
,
Coen Ottenheijm
(23)
,
Thorsten Hoppe
(2)
,
Carsten G. Bönnemann
(1)
1
NINDS -
National Institute of Neurological Disorders and Stroke [Bethesda]
2 University of Cologne
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CHU - Centre Hospitalier Universitaire [Grenoble]
5 GIN - [GIN] Grenoble Institut des Neurosciences
6 CHU Pitié-Salpêtrière [AP-HP]
7 UA - University of Antwerp
8 Mahidol University [Bangkok]
9 UCL - University College of London [London]
10 Newcastle University [Newcastle]
11 Amsterdam UMC - Amsterdam University Medical Center
12 Northwestern University Feinberg School of Medicine
13 Hospital Nacional de Pediatría J.P. Garrahan
14 BROAD INSTITUTE - Broad Institute of MIT and Harvard
15 Hôpital Raymond Poincaré [AP-HP]
16 National Center of Neurology and Psychiatry
17 GU - University of Gothenburg
18 National Center of Neurology and Psychiatry [Tokyo, Japan]
19 University of Messina
20 UniGe - Università degli studi di Genova = University of Genoa
21 IIMCB - International Institute of Molecular and Cell Biology [Warsaw]
22 Centre de recherche en Myologie – U974 SU-INSERM
23 University of Arizona
2 University of Cologne
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CHU - Centre Hospitalier Universitaire [Grenoble]
5 GIN - [GIN] Grenoble Institut des Neurosciences
6 CHU Pitié-Salpêtrière [AP-HP]
7 UA - University of Antwerp
8 Mahidol University [Bangkok]
9 UCL - University College of London [London]
10 Newcastle University [Newcastle]
11 Amsterdam UMC - Amsterdam University Medical Center
12 Northwestern University Feinberg School of Medicine
13 Hospital Nacional de Pediatría J.P. Garrahan
14 BROAD INSTITUTE - Broad Institute of MIT and Harvard
15 Hôpital Raymond Poincaré [AP-HP]
16 National Center of Neurology and Psychiatry
17 GU - University of Gothenburg
18 National Center of Neurology and Psychiatry [Tokyo, Japan]
19 University of Messina
20 UniGe - Università degli studi di Genova = University of Genoa
21 IIMCB - International Institute of Molecular and Cell Biology [Warsaw]
22 Centre de recherche en Myologie – U974 SU-INSERM
23 University of Arizona
Sandra Donkervoort
- Function : Author
- PersonId : 786623
- ORCID : 0000-0001-6399-1444
Xavière Lornage
- Function : Author
- PersonId : 1134141
John Rendu
- Function : Author
- PersonId : 762847
- ORCID : 0000-0002-0377-0807
- IdRef : 147380952
Véronique Bolduc
- Function : Author
- PersonId : 808096
- ORCID : 0000-0003-1690-9270
Johann Böhm
- Function : Author
- PersonId : 1134032
Sarah Djeddi
- Function : Author
- PersonId : 1100647
Henry Houlden
- Function : Author
- PersonId : 763785
- ORCID : 0000-0002-2866-7777
Jocelyn Laporte
- Function : Author
- PersonId : 181385
- IdHAL : jocelyn-laporte
- ORCID : 0000-0001-8256-5862
- IdRef : 131835262
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.