Donkervoort, Sandra, Kutzner, Carl E., Hu, Ying, Lornage, Xaviere, Rendu, John, Stojkovic, Tanya, Baets, Jonathan, Neuhaus, Sarah B., Tanboon, Jantima, Maroofian, Reza, Bolduc, Veronique, Mroczek, Magdalena, Conijn, Stefan, Kuntz, Nancy L., Topf, Ana, Monges, Soledad, Lubieniecki, Fabiana, McCarty, Riley M., Chao, Katherine R., Governali, Serena, Bohm, Johann, Boonyapisit, Kanokwan, Malfatti, Edoardo, Sangruchi, Tumtip, Horkayne-Szakaly, Iren, Hedberg-Oldfors, Carola, Efthymiou, Stephanie, Noguchi, Satoru, Djeddi, Sarah, Iida, Aritoshi, di Rosa, Gabriella, Fiorillo, Chiara ORCID: 0000-0001-9027-343X, Salpietro, Vincenzo, Darin, Niklas, Faure, Julien, Houlden, Henry, Oldfors, Anders, Nishino, Ichizo, de Ridder, Willem, Straub, Volker, Pokrzywa, Wojciech, Laporte, Jocelyn, Foley, A. Reghan, Romero, Norma B., Ottenheijm, Coen, Hoppe, Thorsten ORCID: 0000-0002-4734-9352 and Boennemann, Carsten G. (2020). Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. Am. J. Hum. Genet., 107 (6). S. 1078 - 1096. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Donkervoort, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutzner, Carl E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, YingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lornage, XaviereUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rendu, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stojkovic, TanyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baets, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, Sarah B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tanboon, JantimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolduc, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mroczek, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conijn, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuntz, Nancy L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Topf, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monges, SoledadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubieniecki, FabianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarty, Riley M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chao, Katherine R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Governali, SerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bohm, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boonyapisit, KanokwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malfatti, EdoardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sangruchi, TumtipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horkayne-Szakaly, IrenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hedberg-Oldfors, CarolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noguchi, SatoruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djeddi, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iida, AritoshiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
di Rosa, GabriellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiorillo, ChiaraUNSPECIFIEDorcid.org/0000-0001-9027-343XUNSPECIFIED
Salpietro, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darin, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faure, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oldfors, AndersUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nishino, IchizoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Ridder, WillemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straub, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pokrzywa, WojciechUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laporte, JocelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foley, A. ReghanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romero, Norma B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ottenheijm, CoenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ThorstenUNSPECIFIEDorcid.org/0000-0002-4734-9352UNSPECIFIED
Boennemann, Carsten G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-308743
DOI: 10.1016/j.ajhg.2020.11.002
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 107
Number: 6
Page Range: S. 1078 - 1096
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/30874

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