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Lookup NU author(s): Dr Ana TopfORCiD, Daniel CoxORCiD, Dr Valeria Di Leo, Professor 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.
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
URL: https://doi.org/10.1038/s41588-023-01651-0
DOI: 10.1038/s41588-023-01651-0
Data Access Statement: Due to privacy, ethical and legal issues de-identified patient genomic, transcriptomic and phenotypic data that supports the findings of this study can only be available from the corresponding author upon reasonable request. Zebrafish RNA-seq data can be accessed in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession E-MTAB-12934. Mouse WGS data and human RNA-seq data can be accessed in the Sequence Read Archive under accession (PRJNA1027609 and PRJNA1027754, respectively). Control frequencies and variant information were extracted from gnomAD (v2.1.1; https://gnomad.broadinstitute.org). TTN variant information was obtained from the Leiden Open Variation Database (https://databases.lovd.nl/shared/genes/TTN). Source data are provided with this paper. Code availability All software used to analyze the study data are listed in the Methods and in the Nature Research Reporting Summary and are publicly available.
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