Journal Article

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

O’Donnell-Luria, Anne, Diaz-Manera, Jordi, Barresi, Rita, Smuts, Izelle, Beggs, Alan H., Nakagawa, Osamu, Cooper, Sandra T., Duff, Jennifer, Muntoni, Francesco, Van den Bergh, Peter, Nishino, Ichizo, Oates, Emily C., O’Heir, Emily, Cox, Dan, Marini-Bettolo, Chiara, Cairns, Anita, Henderson, Matt, Busch-Nentwich, Elisabeth M., Sarparanta, Jaakko, Phadke, Rahul, Wraige, Elizabeth, Shah, Snehal, Yoshimura, Kimihiko, Mongini, Tiziana E., Vihola, Anna, Genetti, Casie A., Di Leo, Valeria, Töpf, Ana, Fassad, Mahmoud R., Sealy, Ian M., Lornage, Xavière, Zaharieva, Irina T., Stenton, Sarah L., Manzur, Adnan, Cordell, Heather J., Vilchez, Juan J., Sarkozy, Anna, Bommireddipalli, Shobhana, Bönnemann, Carsten G., Ogonuki, Narumi, Savarese, Marco, Cummings, Beryl B., Sznajer, Yves, Tasca, Giorgio, Jonson, Per Harald, Bodi, Istvan, Martí, Pilar, Nishikawa, Atsuko, Vroling, Bas, Malfatti, Edoardo, Harris, Elizabeth, Patrick, Jane, Erasmus, Corrie E., Schouten, Meyke, Smolnikov, Andrei, Davis, Mark R., Muelas, Nuria, Voermans, Nicol C., Romero, Norma B., Merteroglu, Munise, Kamsteeg, Erik-Jan, Udd, Bjarne, Venturini, Crist

2024

Overview

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. Digenic inheritance of deleterious variants in serine/arginine protein kinase 3 ( SRPK3 ) and titin ( TTN ) leads to a progressive early onset skeletal muscle myopathy. Zebrafish double mutants exhibit a similar myopathy phenotype accompanied by myofibrillar disorganization.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/1516 / 692/699/75/74 / Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Connectin / Connectin - genetics / Connectin - metabolism / Danio rerio / Disease / Females / Gene Function / Genes / Genetic disorders / Genetics / Genotype & phenotype / Heredity / Human Genetics / Humans / Kinases / Life Sciences / Male / Males / Mathematical models / Muscle, Skeletal / Muscles / Muscular Diseases - genetics / Muscular Diseases - metabolism / Muscular Diseases - pathology / Musculoskeletal system / Mutation / Myopathy / Neuromuscular diseases / Phenotypes / Post-transcription / Protein kinase / Proteins / Skeletal muscle / Statistical models / Transcriptomes / Zebrafish / Zebrafish - genetics