Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Ana Töpf; Dan Cox; Irina T. Zaharieva; Valeria Di Leo; Jaakko Sarparanta; Per Harald Jonson; Ian M. Sealy; Andrei Smolnikov; Richard J. White; Anna Vihola; Marco Savarese; Munise Merteroglu; Neha Wali; Kristen M. Laricchia; Cristina Venturini; Bas Vroling; Sarah L. Stenton; Beryl B. Cummings; Elizabeth Harris; Chiara Marini-Bettolo; Jordi Diaz-Manera; Matt Henderson; Rita Barresi; Jennifer Duff; Eleina M. England; Jane Patrick; Sundos Al-Husayni; Valerie Biancalana; Alan H. Beggs; Istvan Bodi; Shobhana Bommireddipalli; Carsten G. Bönnemann; Anita Cairns; Mei Ting Chiew; Kristl G. Claeys; Sandra T. Cooper; Mark R. Davis; Sandra Donkervoort; Corrie E. Erasmus; Mahmoud R. Fassad; Casie A. Genetti; Carla Grosmann; Heinz Jungbluth; Erik Jan Kamsteeg; Xavière Lornage; Wolfgang N. Löscher; Edoardo Malfatti; Adnan Manzur; Pilar Martí; Tiziana E. Mongini; Nuria Muelas; Atsuko Nishikawa; Anne O’Donnell-Luria; Narumi Ogonuki; Gina L. O’Grady; Emily O’Heir; Stéphanie Paquay; Rahul Phadke; Beth A. Pletcher; Norma B. Romero; Meyke Schouten; Snehal Shah; Izelle Smuts; Yves Sznajer; Giorgio Tasca; Robert W. Taylor; Allysa Tuite; Peter Van den Bergh; Grace VanNoy; Nicol C. Voermans; Julia V. Wanschitz; Elizabeth Wraige; Kimihiko Yoshimura; Emily C. Oates; Osamu Nakagawa; Ichizo Nishino; Jocelyn Laporte; Juan J. Vilchez; Daniel G. MacArthur; Anna Sarkozy; Heather J. Cordell; Bjarne Udd; Elisabeth M. Busch-Nentwich; Francesco Muntoni; Volker Straub

doi:10.1038/s41588-023-01651-0

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Ana Töpf^*
, Dan Cox
, Irina T. Zaharieva
, Valeria Di Leo
, Jaakko Sarparanta
, Per Harald Jonson
, Ian M. Sealy
, Andrei Smolnikov
, Richard J. White
, Anna Vihola
, Marco Savarese
, Munise Merteroglu
, Neha Wali
, Kristen M. Laricchia
, Cristina Venturini
, Bas Vroling
, Sarah L. Stenton
, Beryl B. Cummings
, Elizabeth Harris
, Chiara Marini-Bettolo

Jordi Diaz-Manera, Matt Henderson, Rita Barresi, Jennifer Duff, Eleina M. England, Jane Patrick, Sundos Al-Husayni, Valerie Biancalana, Alan H. Beggs, Istvan Bodi, Shobhana Bommireddipalli, Carsten G. Bönnemann, Anita Cairns, Mei Ting Chiew, Kristl G. Claeys, Sandra T. Cooper, Mark R. Davis, Sandra Donkervoort, Corrie E. Erasmus, Mahmoud R. Fassad, Casie A. Genetti, Carla Grosmann, Heinz Jungbluth, Erik Jan Kamsteeg, Xavière Lornage, Wolfgang N. Löscher, Edoardo Malfatti, Adnan Manzur, Pilar Martí, Tiziana E. Mongini, Nuria Muelas, Atsuko Nishikawa, Anne O’Donnell-Luria, Narumi Ogonuki, Gina L. O’Grady, Emily O’Heir, Stéphanie Paquay, Rahul Phadke, Beth A. Pletcher, Norma B. Romero, Meyke Schouten, Snehal Shah, Izelle Smuts, Yves Sznajer, Giorgio Tasca, Robert W. Taylor, Allysa Tuite, Peter Van den Bergh, Grace VanNoy, Nicol C. Voermans, Julia V. Wanschitz, Elizabeth Wraige, Kimihiko Yoshimura, Emily C. Oates, Osamu Nakagawa, Ichizo Nishino, Jocelyn Laporte, Juan J. Vilchez, Daniel G. MacArthur, Anna Sarkozy, Heather J. Cordell, Bjarne Udd, Elisabeth M. Busch-Nentwich, Francesco Muntoni, Volker Straub^*

^*Corresponding author for this work

Newcastle upon Tyne Hospitals NHS Foundation Trust
UCL Great Ormond Street Institute of Child Health
University of Trieste
Folkhalsan Res Ctr, Helsinki
University of Helsinki
Queen Mary University of London
Department of Medicine
Kensington
School of Medicine
University of Padua
Wellcome Sanger Institute
Broad Institute of MIT and Harvard
Massachusetts General Hospital
Division of Infection and Immunity
UCL University College London
Bio-Prodict
Boston Children's Hospital
Northern Genetics Service
Parkinson and Movement Disorders Unit; IRCCS Hospital San Camillo
Harvard Medical School
University of Strasbourg
KCH King's College Hospital NHS Foundation Trust
Childrens Hosp Westmead, Children's Medical Research Institute - Australia
Neuroscience Center, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
Queensland Children’s Hospital
PathWest Laboratory Medicine WA
University Hospitals Leuven
KU Leuven
Donders Institute for Brain, Cognition and Behaviour
Wellcome Trust Centre for Mitochondrial Research
University of California at San Diego
St Thomas' Hospital
GSTT Guy's and St Thomas' NHS Foundation Trust
Randall Centre Cell and Molecular Biophysics
Department of Neurology
Medical University of Innsbruck
Île-de-France
CIBER - Centro de Investigacion Biomedica en Red
Instituto de Investigación Sanitaria Gregorio Marañón (IISGM)
University of Turin
Universitat de València
Hospital Universitario La Paz
National Institute of Neuroscience, Kodaira
RIKEN BioResource Center
National Women's Auckland District Health Board
Laboratoire de Neuropathologie du Développement, Cliniques Universitaires Saint-Luc, University of Louvain Medical School at Brussels, Belgium.
New Jersey Medical School
Groupe Hospitalier Pitié-Salpêtrière
Perth Children's Hospital
Steve Biko Academic Hospital
Nankoku Hospital
National Cerebral and Cardiovascular Center
Garvan Institute of Medical Research
Murdoch Childrens Res Ctr, Murdoch Children's Research Institute
Newcastle University
Great Ormond Street Hospital for Children NHS Foundation Trust

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

19 Citations (Scopus)

Abstract

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3^−/−; ttn.1^+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

Original language	English
Pages (from-to)	395-407
Number of pages	13
Journal	Nature Genetics
Volume	56
Issue number	3
DOIs	https://doi.org/10.1038/s41588-023-01651-0
Publication status	Published - Mar 2024

Access to Document

10.1038/s41588-023-01651-0

Cite this

Töpf, A., Cox, D., Zaharieva, I. T., Di Leo, V., Sarparanta, J., Jonson, P. H., Sealy, I. M., Smolnikov, A., White, R. J., Vihola, A., Savarese, M., Merteroglu, M., Wali, N., Laricchia, K. M., Venturini, C., Vroling, B., Stenton, S. L., Cummings, B. B., Harris, E., ... Straub, V. (2024). Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy. Nature Genetics, 56(3), 395-407. https://doi.org/10.1038/s41588-023-01651-0

@article{316a306a2b604ba0855661ef4ef47a37,

title = "Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy",

abstract = "In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.",

author = "Ana T{\"o}pf and Dan Cox and Zaharieva, \{Irina T.\} and \{Di Leo\}, Valeria and Jaakko Sarparanta and Jonson, \{Per Harald\} and Sealy, \{Ian M.\} and Andrei Smolnikov and White, \{Richard J.\} and Anna Vihola and Marco Savarese and Munise Merteroglu and Neha Wali and Laricchia, \{Kristen M.\} and Cristina Venturini and Bas Vroling and Stenton, \{Sarah L.\} and Cummings, \{Beryl B.\} and Elizabeth Harris and Chiara Marini-Bettolo and Jordi Diaz-Manera and Matt Henderson and Rita Barresi and Jennifer Duff and England, \{Eleina M.\} and Jane Patrick and Sundos Al-Husayni and Valerie Biancalana and Beggs, \{Alan H.\} and Istvan Bodi and Shobhana Bommireddipalli and B{\"o}nnemann, \{Carsten G.\} and Anita Cairns and Chiew, \{Mei Ting\} and Claeys, \{Kristl G.\} and Cooper, \{Sandra T.\} and Davis, \{Mark R.\} and Sandra Donkervoort and Erasmus, \{Corrie E.\} and Fassad, \{Mahmoud R.\} and Genetti, \{Casie A.\} and Carla Grosmann and Heinz Jungbluth and Kamsteeg, \{Erik Jan\} and Xavi{\`e}re Lornage and L{\"o}scher, \{Wolfgang N.\} and Edoardo Malfatti and Adnan Manzur and Pilar Mart{\'i} and Mongini, \{Tiziana E.\} and Nuria Muelas and Atsuko Nishikawa and Anne O{\textquoteright}Donnell-Luria and Narumi Ogonuki and O{\textquoteright}Grady, \{Gina L.\} and Emily O{\textquoteright}Heir and St{\'e}phanie Paquay and Rahul Phadke and Pletcher, \{Beth A.\} and Romero, \{Norma B.\} and Meyke Schouten and Snehal Shah and Izelle Smuts and Yves Sznajer and Giorgio Tasca and Taylor, \{Robert W.\} and Allysa Tuite and \{Van den Bergh\}, Peter and Grace VanNoy and Voermans, \{Nicol C.\} and Wanschitz, \{Julia V.\} and Elizabeth Wraige and Kimihiko Yoshimura and Oates, \{Emily C.\} and Osamu Nakagawa and Ichizo Nishino and Jocelyn Laporte and Vilchez, \{Juan J.\} and MacArthur, \{Daniel G.\} and Anna Sarkozy and Cordell, \{Heather J.\} and Bjarne Udd and Busch-Nentwich, \{Elisabeth M.\} and Francesco Muntoni and Volker Straub",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = mar,

doi = "10.1038/s41588-023-01651-0",

language = "English",

volume = "56",

pages = "395--407",

journal = "Nature Genetics",

issn = "1061-4036",

number = "3",

}

Töpf, A, Cox, D, Zaharieva, IT, Di Leo, V, Sarparanta, J, Jonson, PH, Sealy, IM, Smolnikov, A, White, RJ, Vihola, A, Savarese, M, Merteroglu, M, Wali, N, Laricchia, KM, Venturini, C, Vroling, B, Stenton, SL, Cummings, BB, Harris, E, Marini-Bettolo, C, Diaz-Manera, J, Henderson, M, Barresi, R, Duff, J, England, EM, Patrick, J, Al-Husayni, S, Biancalana, V, Beggs, AH, Bodi, I, Bommireddipalli, S, Bönnemann, CG, Cairns, A, Chiew, MT, Claeys, KG, Cooper, ST, Davis, MR, Donkervoort, S, Erasmus, CE, Fassad, MR, Genetti, CA, Grosmann, C, Jungbluth, H, Kamsteeg, EJ, Lornage, X, Löscher, WN, Malfatti, E, Manzur, A, Martí, P, Mongini, TE, Muelas, N, Nishikawa, A, O’Donnell-Luria, A, Ogonuki, N, O’Grady, GL, O’Heir, E, Paquay, S, Phadke, R, Pletcher, BA, Romero, NB, Schouten, M, Shah, S, Smuts, I, Sznajer, Y, Tasca, G, Taylor, RW, Tuite, A, Van den Bergh, P, VanNoy, G, Voermans, NC, Wanschitz, JV, Wraige, E, Yoshimura, K, Oates, EC, Nakagawa, O, Nishino, I, Laporte, J, Vilchez, JJ, MacArthur, DG, Sarkozy, A, Cordell, HJ, Udd, B, Busch-Nentwich, EM, Muntoni, F & Straub, V 2024, 'Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy', Nature Genetics, vol. 56, no. 3, pp. 395-407. https://doi.org/10.1038/s41588-023-01651-0

TY - JOUR

T1 - Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

AU - Töpf, Ana

AU - Cox, Dan

AU - Zaharieva, Irina T.

AU - Di Leo, Valeria

AU - Sarparanta, Jaakko

AU - Jonson, Per Harald

AU - Sealy, Ian M.

AU - Smolnikov, Andrei

AU - White, Richard J.

AU - Vihola, Anna

AU - Savarese, Marco

AU - Merteroglu, Munise

AU - Wali, Neha

AU - Laricchia, Kristen M.

AU - Venturini, Cristina

AU - Vroling, Bas

AU - Stenton, Sarah L.

AU - Cummings, Beryl B.

AU - Harris, Elizabeth

AU - Marini-Bettolo, Chiara

AU - Diaz-Manera, Jordi

AU - Henderson, Matt

AU - Barresi, Rita

AU - Duff, Jennifer

AU - England, Eleina M.

AU - Patrick, Jane

AU - Al-Husayni, Sundos

AU - Biancalana, Valerie

AU - Beggs, Alan H.

AU - Bodi, Istvan

AU - Bommireddipalli, Shobhana

AU - Bönnemann, Carsten G.

AU - Cairns, Anita

AU - Chiew, Mei Ting

AU - Claeys, Kristl G.

AU - Cooper, Sandra T.

AU - Davis, Mark R.

AU - Donkervoort, Sandra

AU - Erasmus, Corrie E.

AU - Fassad, Mahmoud R.

AU - Genetti, Casie A.

AU - Grosmann, Carla

AU - Jungbluth, Heinz

AU - Kamsteeg, Erik Jan

AU - Lornage, Xavière

AU - Löscher, Wolfgang N.

AU - Malfatti, Edoardo

AU - Manzur, Adnan

AU - Martí, Pilar

AU - Mongini, Tiziana E.

AU - Muelas, Nuria

AU - Nishikawa, Atsuko

AU - O’Donnell-Luria, Anne

AU - Ogonuki, Narumi

AU - O’Grady, Gina L.

AU - O’Heir, Emily

AU - Paquay, Stéphanie

AU - Phadke, Rahul

AU - Pletcher, Beth A.

AU - Romero, Norma B.

AU - Schouten, Meyke

AU - Shah, Snehal

AU - Smuts, Izelle

AU - Sznajer, Yves

AU - Tasca, Giorgio

AU - Taylor, Robert W.

AU - Tuite, Allysa

AU - Van den Bergh, Peter

AU - VanNoy, Grace

AU - Voermans, Nicol C.

AU - Wanschitz, Julia V.

AU - Wraige, Elizabeth

AU - Yoshimura, Kimihiko

AU - Oates, Emily C.

AU - Nakagawa, Osamu

AU - Nishino, Ichizo

AU - Laporte, Jocelyn

AU - Vilchez, Juan J.

AU - MacArthur, Daniel G.

AU - Sarkozy, Anna

AU - Cordell, Heather J.

AU - Udd, Bjarne

AU - Busch-Nentwich, Elisabeth M.

AU - Muntoni, Francesco

AU - Straub, Volker

PY - 2024/3

Y1 - 2024/3

N2 - In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

AB - In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

UR - https://www.scopus.com/pages/publications/85186444099

U2 - 10.1038/s41588-023-01651-0

DO - 10.1038/s41588-023-01651-0

M3 - Article

C2 - 38429495

AN - SCOPUS:85186444099

SN - 1061-4036

VL - 56

SP - 395

EP - 407

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Abstract

Access to Document

Other files and links

Fingerprint

Cite this