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

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

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
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
Publication status	Published - Dec 3 2020

Keywords

Adolescent
Adult
Alleles
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins/genetics
Female
Genetic Variation
Humans
Loss of Function Mutation
Male
Molecular Chaperones/genetics
Muscle, Skeletal/pathology
Muscular Diseases/genetics
Mutation, Missense
Myofibrils
Myosins
Sarcomeres/metabolism
Sequence Analysis, RNA
Transgenes
Whole Exome Sequencing
Young Adult

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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

Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. / Donkervoort, Sandra; Kutzner, Carl E; Hu, Ying; Lornage, Xavière; Rendu, John; Stojkovic, Tanya; Baets, Jonathan; Neuhaus, Sarah B; Tanboon, Jantima; Maroofian, Reza; Bolduc, Véronique; Mroczek, Magdalena; Conijn, Stefan; Kuntz, Nancy L; Töpf, Ana; Monges, Soledad; Lubieniecki, Fabiana; McCarty, Riley M; Chao, Katherine R; Governali, Serena; Böhm, 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 ; Salpietro, Vincenzo; Darin, Niklas; Fauré, 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; Bönnemann, Carsten G.

In: American Journal of Human Genetics, Vol. 107, No. 6, 03.12.2020, p. 1078-1095.

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

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

Donkervoort, Sandra ; Kutzner, Carl E ; Hu, Ying ; Lornage, Xavière ; Rendu, John ; Stojkovic, Tanya ; Baets, Jonathan ; Neuhaus, Sarah B ; Tanboon, Jantima ; Maroofian, Reza ; Bolduc, Véronique ; Mroczek, Magdalena ; Conijn, Stefan ; Kuntz, Nancy L ; Töpf, Ana ; Monges, Soledad ; Lubieniecki, Fabiana ; McCarty, Riley M ; Chao, Katherine R ; Governali, Serena ; Böhm, 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 ; Salpietro, Vincenzo ; Darin, Niklas ; Fauré, 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 ; Bönnemann, Carsten G. / Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores. In: American Journal of Human Genetics. 2020 ; Vol. 107, No. 6. pp. 1078-1095.

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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 = "Adolescent, Adult, Alleles, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins/genetics, Female, Genetic Variation, Humans, Loss of Function Mutation, Male, Molecular Chaperones/genetics, Muscle, Skeletal/pathology, Muscular Diseases/genetics, Mutation, Missense, Myofibrils, Myosins, Sarcomeres/metabolism, Sequence Analysis, RNA, Transgenes, Whole Exome Sequencing, Young Adult",

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}",

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

language = "English",

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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 - Adolescent

KW - Adult

KW - Alleles

KW - Animals

KW - Caenorhabditis elegans

KW - Caenorhabditis elegans Proteins/genetics

KW - Female

KW - Genetic Variation

KW - Humans

KW - Loss of Function Mutation

KW - Male

KW - Molecular Chaperones/genetics

KW - Muscle, Skeletal/pathology

KW - Muscular Diseases/genetics

KW - Mutation, Missense

KW - Myofibrils

KW - Myosins

KW - Sarcomeres/metabolism

KW - Sequence Analysis, RNA

KW - Transgenes

KW - Whole Exome Sequencing

KW - Young Adult

U2 - 10.1016/j.ajhg.2020.11.002

DO - 10.1016/j.ajhg.2020.11.002

M3 - Article

C2 - 33217308

VL - 107

SP - 1078

EP - 1095

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -