Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
Sandra Donkervoort
(1)
,
Carl Kutzner
(2)
,
Ying Hu
(1)
,
Xavière Lornage
(3)
,
John Rendu
(4, 5)
,
Tanya Stojkovic
(6, 7)
,
Jonathan Baets
(8, 9)
,
Sarah Neuhaus
(1)
,
Jantima Tanboon
(10, 11)
,
Reza Maroofian
(12)
,
Véronique Bolduc
(1)
,
Magdalena Mroczek
(13)
,
Stefan Conijn
(14)
,
Nancy Kuntz
(15)
,
Ana Töpf
(13)
,
Soledad Monges
(16)
,
Fabiana Lubieniecki
(16)
,
Riley Mccarty
(1)
,
Katherine Chao
(17)
,
Serena Governali
(14)
,
Johann Böhm
(3)
,
Kanokwan Boonyapisit
(10, 11)
,
Edoardo Malfatti
(18)
,
Tumtip Sangruchi
(10, 11)
,
Iren Horkayne-Szakaly
,
Carola Hedberg-Oldfors
(19)
,
Stephanie Efthymiou
(12)
,
Satoru Noguchi
(20)
,
Sarah Djeddi
(3)
,
Aritoshi Iida
(20)
,
Gabriella Di Rosa
(21)
,
Chiara Fiorillo
(22)
,
Vincenzo Salpietro
(22)
,
Niklas Darin
(19)
,
Julien Fauré
(4, 5)
,
Henry Houlden
(12)
,
Anders Oldfors
(19)
,
Ichizo Nishino
(20)
,
Willem de Ridder
(8, 9)
,
Volker Straub
(13, 23)
,
Wojciech Pokrzywa
(24)
,
Jocelyn Laporte
(3)
,
A. Reghan Foley
(1)
,
Norma Romero
(25, 6, 26)
,
Coen Ottenheijm
(27, 14)
,
Thorsten Hoppe
(2)
,
Carsten 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 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
5 GIN - [GIN] Grenoble Institut des Neurosciences
6 CHU Pitié-Salpêtrière [AP-HP]
7 SU - Sorbonne Université
8 UA - University of Antwerp
9 UZA - Antwerp University Hospital [Edegem]
10 Mahidol University [Bangkok]
11 Siriraj Hospital, Mahidol University
12 UCL - University College of London [London]
13 Newcastle University [Newcastle]
14 Amsterdam UMC - Amsterdam University Medical Centers
15 Northwestern University [Evanston]
16 Hospital Nacional de Pediatría J.P. Garrahan
17 BROAD INSTITUTE - Broad Institute of MIT and Harvard
18 Hôpital Raymond Poincaré [AP-HP]
19 Sahlgrenska Academy at University of Gothenburg [Göteborg]
20 National Center of Neurology and Psychiatry [Tokyo, Japan]
21 University of Messina
22 UniGe - Università degli studi di Genova = University of Genoa
23 Newcastle Upon Tyne Hospitals NHS Foundation Trust
24 IIMCB - International Institute of Molecular and Cell Biology [Warsaw]
25 Institut de Myologie
26 Centre de recherche en Myologie – U974 SU-INSERM
27 University of Arizona
2 University of Cologne
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
5 GIN - [GIN] Grenoble Institut des Neurosciences
6 CHU Pitié-Salpêtrière [AP-HP]
7 SU - Sorbonne Université
8 UA - University of Antwerp
9 UZA - Antwerp University Hospital [Edegem]
10 Mahidol University [Bangkok]
11 Siriraj Hospital, Mahidol University
12 UCL - University College of London [London]
13 Newcastle University [Newcastle]
14 Amsterdam UMC - Amsterdam University Medical Centers
15 Northwestern University [Evanston]
16 Hospital Nacional de Pediatría J.P. Garrahan
17 BROAD INSTITUTE - Broad Institute of MIT and Harvard
18 Hôpital Raymond Poincaré [AP-HP]
19 Sahlgrenska Academy at University of Gothenburg [Göteborg]
20 National Center of Neurology and Psychiatry [Tokyo, Japan]
21 University of Messina
22 UniGe - Università degli studi di Genova = University of Genoa
23 Newcastle Upon Tyne Hospitals NHS Foundation Trust
24 IIMCB - International Institute of Molecular and Cell Biology [Warsaw]
25 Institut de Myologie
26 Centre de recherche en Myologie – U974 SU-INSERM
27 University of Arizona
Sandra Donkervoort
- Fonction : Auteur
- PersonId : 786623
- ORCID : 0000-0001-6399-1444
Xavière Lornage
- Fonction : Auteur
- PersonId : 1134141
John Rendu
- Fonction : Auteur
- PersonId : 762847
- ORCID : 0000-0002-0377-0807
- IdRef : 147380952
Véronique Bolduc
- Fonction : Auteur
- PersonId : 808096
- ORCID : 0000-0003-1690-9270
Johann Böhm
- Fonction : Auteur
- PersonId : 1134032
Tumtip Sangruchi
- Fonction : Auteur
Iren Horkayne-Szakaly
- Fonction : Auteur
Sarah Djeddi
- Fonction : Auteur
- PersonId : 1100647
Julien Fauré
- Fonction : Auteur
- PersonId : 1415517
- IdHAL : julienfaure
- ORCID : 0000-0002-3660-9809
Henry Houlden
- Fonction : Auteur
- PersonId : 763785
- ORCID : 0000-0002-2866-7777
Jocelyn Laporte
- Fonction : Auteur
- PersonId : 181385
- IdHAL : jocelyn-laporte
- ORCID : 0000-0001-8256-5862
- IdRef : 131835262
Résumé
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.
| Origine | Fichiers produits par l'(les) auteur(s) |
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