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

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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

Alkuperäiskielienglanti
LehtiNature Genetics
Vuosikerta56
Numero3
Sivut395-407
Sivumäärä13
ISSN1061-4036
DOI - pysyväislinkit
TilaJulkaistu - maalisk. 2024
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lisätietoja

Publisher Copyright:
© The Author(s) 2024.

Tieteenalat

  • 1184 Genetiikka, kehitysbiologia, fysiologia

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