Nature genetics · 2024

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

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

Аннотация

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.

Предметные рубрики MeSH

Animals Humans Male Connectin Muscle, Skeletal Muscular Diseases Mutation Zebrafish

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

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Аннотация

Предметные рубрики MeSH