Digenic muscular dystrophy due to SRPK3 and TTN variants

Inspired by a patient

Töpf A, Cox D, Zaharieva IT, Di Leo V, Sarparanta J, Jonson PH, Sealy IM, Smolnikov A, White RJ, Vihola A, Savarese M, Merteroglu M, Wali N, Laricchia KM, Venturini C, Vroling B, Stenton SL, Cummings BB, Harris E, Marini-Bettolo C, Diaz-Manera J, Henderson M, Barresi R, Duff J, England EM, Patrick J, Al-Husayni S, Biancalana V, Beggs AH, Bodi I, Bommireddipalli S, Bönnemann CG, Cairns A, Chiew MT, Claeys KG, Cooper ST, Davis MR, Donkervoort S, Erasmus CE, Fassad MR, Genetti CA, Grosmann C, Jungbluth H, Kamsteeg EJ, Lornage X, Löscher WN, Malfatti E, Manzur A, Martí P, Mongini TE, Muelas N, Nishikawa A, O'Donnell-Luria A, Ogonuki N, O'Grady GL, O'Heir E, Paquay S, Phadke R, Pletcher BA, Romero NB, Schouten M, Shah S, Smuts I, Sznajer Y, Tasca G, Taylor RW, Tuite A, Van den Bergh P, VanNoy G, Voermans NC, Wanschitz JV, Wraige E, Yoshimura K, Oates EC, Nakagawa O, Nishino I, Laporte J, Vilchez JJ, MacArthur DG, Sarkozy A, Cordell HJ, Udd B, Busch-Nentwich EM, Muntoni F, Straub V. Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy. Nat Genet. 2024 Mar;56(3):395-407. doi: 10.1038/s41588-023-01651-0. Epub 2024 Mar 1. PMID: 38429495; PMCID: PMC10937387.

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.

Sharkova I, Borovikov A, Konovalov F, Nefedova M, Shchagina O, Kutsev S, Murtazina A. Clinical and Genetic Analysis of Digenic Muscular Dystrophy due to SRPK3 and TTN Variants in Two Siblings. Clin Genet. 2025 May;107(5):547-551. doi: 10.1111/cge.14673. Epub 2024 Dec 12. PMID: 39667923.

Abstract

We present a family with two male siblings diagnosed with a newly described digenic myopathy, involving likely pathogenic loss-of-function variants in the SRPK3 and TTN genes: hemizygous p.(Pro68ArgfsTer55) and heterozygous p.(Trp14174Ter), respectively. Both siblings experienced prenatal disease onset, characterized by weak fetal movements, but showed significant clinical improvement over two last years of our follow-up. Key features included early onset, delayed motor development, and prominent axial and proximal weakness, while adult variants' carriers remained asymptomatic, without any myopathic or cardiac manifestations. Lower limb MRI revealed distinctive abnormalities, with different patterns between the siblings: the older brother showed more pronounced involvement of the thigh muscles, while the younger brother exhibited greater changes in the lower leg muscles. Given the early stage of the disease in our patients and the initial changes observed on MRI, we suggest that the semitendinosus and vastus lateralis muscles are primarily involved at the thigh level in SRPK3/TTN-myopathy. This case highlights the importance of considering digenic inheritance in neuromuscular disorders and underscores the necessity of comprehensive genetic analysis in similar cases.