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

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^-/-; 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.

SUBMITTER: Topf A

PROVIDER: S-EPMC10937387 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20240301 3

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 ...[more]

PMID: 38429495

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Project description:Purpose: Ribosome profiling and RNA-Seq were used to map the location and abundance of translating ribosomes on mouse heart and skeletal muscle transcripts. Methods: Tissue was rapidly harvested and snap-frozen to minimize bias to the pool of translating ribosomes. RNA was prepared from a single homogenate for each tissue so that starting RNA populations for both libraries were closely matched. Homogenates were not clarified before RNase digestion to avoid loss of ribosomes associated with large molecular weight complexes, and RNA-Seq libraries were prepared after rRNA subtraction to avoid positional loss of 5’ reads. Trimmed reads from 50 cycles of Illumina single-end sequencing were mapped onto a non-redundant set of 18,499 mouse protein-coding RefSeq transcripts from the nuclear genome. Results: Mapped sequence reads to myosin, actin and the giant protein titin together account for ~20% of the total mRNA-derived ribosome protected fragments (RPFs). We observed large-scale uniformity in the distribution of RPFs on the >30,000 codon titin open reading frame, from which we inferred an in vivo ribosome elongation error rate of ≤10-5. Ribosome footprints on Ttn mRNA also uncovered a novel 5’ UTR within a phylogenetically conserved intronic element that would produce ~2.35 mDa titin isoform that corresponds to the titin 'T2' band frequently described as a proteolytic artifact. Local translation efficiency across several >10 kb muscle mRNAs was also uniform, while their global translation efficiencies varied by ~20-fold suggesting initiation rate plays a major role in the translation efficiency of large mRNAs. Evidence for RPFs on 5’ UTRs was widespread with particular enrichment for ribosomes positioned at CUG codons. Comparison of global translation efficiency in cardiac and skeletal muscle revealed novel examples of tissue-specific translational control including synthesis of the myogenic factor Mef2c, and the titin-binding stress response protein Ankrd23. Conclusions: Our study represents the first detailed analysis of translation in an adult mammalian tissue generated by ribosome profiling technology. Current limitations to using ribosomal profiling in tissues include unknown perturbations to the dynamic state of translation despite rapidly harvested and snap-frozen samples. The uniform 5’ to 3’ coverage observed on individual large mRNAs and the ability to observe footprints on the extremely small phospholamban coding sequence, suggests that initiation and elongation were halted on similar time scales. More detailed examination of the positional information within CDS region requires further understanding of the bias introduced during the library preparation steps for both RPF-and RNA-Seq, as well as local biases induced as translation is arrested. Despite these qualifications, this initial view of active translation in muscle tissue highlights the potential for ribosome profiling to monitor the dynamic translation response to exercise, injury or disease pathology in animal models at a level of resolution not easily attainable with other quantitative approaches. Heart and skeletal muscle ribosome-protected fragment and RNA-Seq profiles of 10-week old C57BL/6J male mice were generated by deep sequencing using the Illumina HiSeq 2000.

Dataset Information

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

Publications

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

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