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

Sandra Donkervoort; Carl E. Kutzner; Ying Hu; Xavière Lornage; John Rendu; Tanya Stojkovic; Jonathan Baets; Sarah B. Neuhaus; Jantima Tanboon; Reza Maroofian; Véronique Bolduc; Magdalena Mroczek; Stefan Conijn; Nancy L. Kuntz; Ana Töpf; Soledad Monges; Fabiana Lubieniecki; Riley M. McCarty; Katherine R. Chao; Serena Governali; Johann Böhm; Kanokwan Boonyapisit; Edoardo Malfatti; Tumtip Sangruchi; Iren Horkayne-Szakaly; Carola Hedberg-Oldfors; Stephanie Efthymiou; Satoru Noguchi; Sarah Djeddi; Aritoshi Iida; Gabriella di Rosa; Chiara Fiorillo; Vincenzo Salpietro; Niklas Darin; Julien Fauré; Henry Houlden; Anders Oldfors; Ichizo Nishino; Willem de Ridder; Volker Straub; Wojciech Pokrzywa; Jocelyn Laporte; A. Reghan Foley; Norma B. Romero; Coen Ottenheijm; Thorsten Hoppe; Carsten G. Bönnemann

doi:10.1016/j.ajhg.2020.11.002

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

Sandra Donkervoort, Carl E. Kutzner, Ying Hu, Xavière Lornage, John Rendu, Tanya Stojkovic, Jonathan Baets, Sarah B. Neuhaus, Jantima Tanboon, Reza Maroofian, Véronique Bolduc, Magdalena Mroczek, Stefan Conijn, Nancy L. Kuntz, Ana Töpf, Soledad Monges, Fabiana Lubieniecki, Riley M. McCarty, Katherine R. Chao, Serena GovernaliJohann Böhm, Kanokwan Boonyapisit, Edoardo Malfatti, Tumtip Sangruchi, Iren Horkayne-Szakaly, Carola Hedberg-Oldfors, Stephanie Efthymiou, Satoru Noguchi, Sarah Djeddi, Aritoshi Iida, Gabriella di Rosa, Chiara Fiorillo, Vincenzo Salpietro, Niklas Darin, Julien Fauré, Henry Houlden, Anders Oldfors, Ichizo Nishino, Willem de Ridder, Volker Straub, Wojciech Pokrzywa, Jocelyn Laporte, A. Reghan Foley, Norma B. Romero, Coen Ottenheijm, Thorsten Hoppe^*, Carsten G. Bönnemann^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1078-1095
Number of pages	18
Journal	American journal of human genetics
Volume	107
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2020.11.002
State	Published - Dec 3 2020

Funding

We thank the individuals and their families for participating in our research study and Christopher Mendoza, Christine Jones, Gilberto (\u201CMike\u201D) Averion, Rupleen Kaur, Kia Brooks, and Janelle Geist Hauserman for their help in the clinic and the laboratory. We would like to thank the CHUGA Molecular Biology facility platform for their help with exome sequencing. We thank Y. Kohara, the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources), the Dana-Farber Cancer Institute, and Addgene and Geneservice for plasmids, cDNAs, and worm strains. We thank the CECAD Imaging facility for support with confocal microscopy. In particular, we thank Vishnu Balaji for the purification of LET-70-HIS and VSV-CHN-1-HIS proteins and help with in vitro studies. For the complete Acknowledgments including funding sources, please see Supplemental Information .

Keywords

C. elegans
UNC-45
UNC45B
chaperone
core myopathy
muscle
myofibrillar
myosin
sarcomere

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2020.11.002

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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., Töpf, A., Monges, S., Lubieniecki, F., McCarty, R. M., Chao, K. R., ... Bönnemann, C. G. (2020). Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. American journal of human genetics, 107(6), 1078-1095. https://doi.org/10.1016/j.ajhg.2020.11.002

@article{5e2b31bf0d9c4a2f89ea85a080f669e1,

title = "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.",

keywords = "C. elegans, UNC-45, UNC45B, chaperone, core myopathy, muscle, myofibrillar, myosin, sarcomere",

author = "Sandra Donkervoort and Kutzner, {Carl E.} and Ying Hu and Xavi{\`e}re Lornage and John Rendu and Tanya Stojkovic and Jonathan Baets and Neuhaus, {Sarah B.} and Jantima Tanboon and Reza Maroofian and V{\'e}ronique Bolduc and Magdalena Mroczek and Stefan Conijn and Kuntz, {Nancy L.} and Ana T{\"o}pf and Soledad Monges and Fabiana Lubieniecki and McCarty, {Riley M.} and Chao, {Katherine R.} and Serena Governali and Johann B{\"o}hm and Kanokwan Boonyapisit and Edoardo Malfatti and Tumtip Sangruchi and Iren Horkayne-Szakaly and Carola Hedberg-Oldfors and Stephanie Efthymiou and Satoru Noguchi and Sarah Djeddi and Aritoshi Iida and {di Rosa}, Gabriella and Chiara Fiorillo and Vincenzo Salpietro and Niklas Darin and Julien Faur{\'e} and Henry Houlden and Anders Oldfors and Ichizo Nishino and {de Ridder}, Willem and Volker Straub and Wojciech Pokrzywa and Jocelyn Laporte and Foley, {A. Reghan} and Romero, {Norma B.} and Coen Ottenheijm and Thorsten Hoppe and B{\"o}nnemann, {Carsten G.}",

note = "Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = dec,

day = "3",

doi = "10.1016/j.ajhg.2020.11.002",

language = "English (US)",

volume = "107",

pages = "1078--1095",

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Donkervoort, S, Kutzner, CE, Hu, Y, Lornage, X, Rendu, J, Stojkovic, T, Baets, J, Neuhaus, SB, Tanboon, J, Maroofian, R, Bolduc, V, Mroczek, M, Conijn, S, Kuntz, NL, Töpf, A, Monges, S, Lubieniecki, F, McCarty, RM, Chao, KR, Governali, S, Böhm, 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, Fauré, J, Houlden, H, Oldfors, A, Nishino, I, de Ridder, W, Straub, V, Pokrzywa, W, Laporte, J, Foley, AR, Romero, NB, Ottenheijm, C, Hoppe, T & Bönnemann, CG 2020, 'Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores', American journal of human genetics, vol. 107, no. 6, pp. 1078-1095. https://doi.org/10.1016/j.ajhg.2020.11.002

TY - JOUR

T1 - Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

AU - Donkervoort, Sandra

AU - Kutzner, Carl E.

AU - Hu, Ying

AU - Lornage, Xavière

AU - Rendu, John

AU - Stojkovic, Tanya

AU - Baets, Jonathan

AU - Neuhaus, Sarah B.

AU - Tanboon, Jantima

AU - Maroofian, Reza

AU - Bolduc, Véronique

AU - Mroczek, Magdalena

AU - Conijn, Stefan

AU - Kuntz, Nancy L.

AU - Töpf, Ana

AU - Monges, Soledad

AU - Lubieniecki, Fabiana

AU - McCarty, Riley M.

AU - Chao, Katherine R.

AU - Governali, Serena

AU - Böhm, Johann

AU - Boonyapisit, Kanokwan

AU - Malfatti, Edoardo

AU - Sangruchi, Tumtip

AU - Horkayne-Szakaly, Iren

AU - Hedberg-Oldfors, Carola

AU - Efthymiou, Stephanie

AU - Noguchi, Satoru

AU - Djeddi, Sarah

AU - Iida, Aritoshi

AU - di Rosa, Gabriella

AU - Fiorillo, Chiara

AU - Salpietro, Vincenzo

AU - Darin, Niklas

AU - Fauré, Julien

AU - Houlden, Henry

AU - Oldfors, Anders

AU - Nishino, Ichizo

AU - de Ridder, Willem

AU - Straub, Volker

AU - Pokrzywa, Wojciech

AU - Laporte, Jocelyn

AU - Foley, A. Reghan

AU - Romero, Norma B.

AU - Ottenheijm, Coen

AU - Hoppe, Thorsten

AU - Bönnemann, Carsten G.

PY - 2020/12/3

Y1 - 2020/12/3

N2 - 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.

AB - 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.

KW - C. elegans

KW - UNC-45

KW - UNC45B

KW - chaperone

KW - core myopathy

KW - muscle

KW - myofibrillar

KW - myosin

KW - sarcomere

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UR - http://www.scopus.com/inward/citedby.url?scp=85097368013&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2020.11.002

DO - 10.1016/j.ajhg.2020.11.002

M3 - Article

C2 - 33217308

AN - SCOPUS:85097368013

SN - 0002-9297

VL - 107

SP - 1078

EP - 1095

JO - American journal of human genetics

JF - American journal of human genetics

IS - 6

ER -

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

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