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

Lookup NU author(s): Dr Ana TopfORCiD, Daniel CoxORCiD, Dr Valeria Di Leo, Dr Chiara Marini Bettolo, Professor Jordi Diaz ManeraORCiD, Matt Henderson, Dr Jennifer Duff, Dr Mahmoud FassadORCiD, Professor Giorgio TascaORCiD, Professor Robert Taylor, Professor Heather Cordell, Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2024.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.

Publication metadata

Author(s): Topf 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, Bonnemann CG, Cairns A, Chiew M-T, Claeys KG, Cooper ST, Davis MR, Donkervoort S, Erasmus CE, Fassad MR, Genetti CA, Grosmann C, Jungbluth H, Kamsteeg E-J, Lornage X, Loscher WN, Malfatti E, Manzur A, Marti 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

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2024

Volume: 56

Pages: 395–407

Print publication date: 01/03/2024

Online publication date: 01/03/2024

Acceptance date: 19/12/2023

Date deposited: 19/03/2024

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Research


DOI: 10.1038/s41588-023-01651-0


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
779257European Commission
BB/R013942/1Biotechnology and Biological Sciences Research Council (BBSRC)
European Community Seventh Framework Program
European Union Horizon 2020
Lily Foundation
Medical Research Council
Medical Research Council International Center for Genomic Medicine in Neuromuscular Disease
Mito Foundation
Mitochondrial Disease Patient Cohort
MR/S005021/1Medical Research Council (MRC)
NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children
Pathological Society
NIHR Biomedical Research Center for Ageing and Age-related Disease
NIHR Newcastle Biomedical Research Center
Wellcome Center for Mitochondrial Research