Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
Ana TopfDan CoxIrina T ZaharievaValeria Di LeoJaakko SarparantaPer Harald JonsonIan M SealyAndrei SmolnikovRichard J WhiteAnna ViholaMarco SavareseMunise MerterogluNeha WaliKristen M LaricchiaCristina VenturiniBas VrolingSarah L StentonBeryl B CummingsElizabeth HarrisChiara Marini-BettoloJordi Diaz-ManeraMatt HendersonRita BarresiJennifer DuffEleina M EnglandJane PatrickSundos Al-HusayniValerie BiancalanaAlan H BeggsIstvan BodiShobhana BommireddipalliCarsten G BonnemannAnita CairnsMei-Ting ChiewKristl G ClaeysSandra T CooperMark R DavisSandra DonkervoortCorrie E ErasmusMahmoud R FassadCasie A GenettiCarla GrosmannHeinz JungbluthErik-Jan KamsteegXavière LornageWolfgang N LöscherEdoardo MalfattiAdnan ManzurPilar MartíTiziana E MonginiNuria MuelasAtsuko NishikawaAnne H O'Donnell-LuriaNarumi OgonukiGina L O'GradyEmily O'HeirStéphanie PaquayRahul PhadkeBeth A PletcherNorma B RomeroMeyke SchoutenSnehal ShahIzelle SmutsYves SznajerGiorgio TascaRobert W TaylorAllysa TuitePeter Van den BerghGrace VanNoyNicol C VoermansJulia V WanschitzElizabeth WraigeKimihiko YoshimuraEmily C OatesOsamu NakagawaIchizo NishinoJocelyn LaporteJuan Jesus VilchezDaniel G MacArthurAnna SarkozyHeather J CordellBjarne UddElisabeth M Busch-NentwichFrancesco MuntoniVolker StraubPublished in: Nature genetics (2024)
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.
Keyphrases
- copy number
- mitochondrial dna
- protein kinase
- skeletal muscle
- early onset
- genome wide
- late onset
- dna methylation
- insulin resistance
- gene expression
- multiple sclerosis
- muscular dystrophy
- protein protein
- small molecule
- single cell
- electronic health record
- rna seq
- metabolic syndrome
- amino acid
- big data
- machine learning
- artificial intelligence
- binding protein