{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Topf A"],"funding":["NICHD NIH HHS","Medical Research Council","NHGRI NIH HHS","National Institute for Health Research (NIHR)","Rosetrees","Muscular Dystrophy UK","Wellcome Trust","Biotechnology and Biological Sciences Research Council"],"pagination":["395-407"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10937387"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["56(3)"],"pubmed_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<sup>-/-</sup>; ttn.1<sup>+/-</sup>) 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."],"journal":["Nature genetics"],"pubmed_title":["Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy."],"pmcid":["PMC10937387"],"funding_grant_id":["NIHR202446","M145","18GRO-PG24-0271","MR/S005021/1","R01 HG009141","U01 HG011755","MR/W019027/1","BB/R013942/1","G0800674","U54 HD090255","UM1 HG008900"],"pubmed_authors":["Busch-Nentwich EM","Shah S","Wanschitz JV","Nakagawa O","Bonnemann CG","Patrick J","Romero NB","Tuite A","Cordell HJ","Claeys KG","Lornage X","Cummings BB","Fassad MR","Genetti CA","Voermans NC","Topf A","Bommireddipalli S","Grosmann C","Savarese M","Diaz-Manera J","Straub V","Cairns A","Tasca G","Schouten M","Oates EC","MacArthur DG","Muelas N","Barresi R","Cooper ST","Yoshimura K","Sarparanta J","Vilchez JJ","Vihola A","Wali N","VanNoy G","Udd B","Biancalana V","Sznajer Y","Merteroglu M","Henderson M","Bodi I","Duff J","Vroling B","Nishino I","Chiew MT","Donkervoort S","Laporte J","Sarkozy A","Al-Husayni S","Di Leo V","Jonson PH","Sealy IM","O'Heir E","England EM","Loscher WN","Phadke R","Van den Bergh P","Laricchia KM","O'Grady GL","Jungbluth H","Marti P","Pletcher BA","White RJ","Nishikawa A","Manzur A","Malfatti E","Stenton SL","Davis MR","Smolnikov A","Ogonuki N","Zaharieva IT","O'Donnell-Luria A","Paquay S","Wraige E","Muntoni F","Venturini C","Smuts I","Beggs AH","Cox D","Marini-Bettolo C","Taylor RW","Harris E","Mongini TE","Erasmus CE","Kamsteeg EJ"],"additional_accession":[]},"is_claimable":false,"name":"Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.","description":"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<sup>-/-</sup>; ttn.1<sup>+/-</sup>) 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-07-01T03:22:01.625Z","creation":"2026-07-01T03:07:44.77Z"},"accession":"S-EPMC10937387","cross_references":{"pubmed":["38429495"],"doi":["10.1038/s41588-023-01651-0"]}}