Kim, Hong JooHong JooKimMohassel, PayamPayamMohasselDonkervoort, SandraSandraDonkervoortGuo, LinLinGuoO'Donovan, KevinKevinO'DonovanCoughlin, MauraMauraCoughlinLornage, XaviereXaviereLornageFoulds, NicolaNicolaFouldsHammans, Simon RSimon RHammansFoley, A ReghanA ReghanFoleyFare, Charlotte MCharlotte MFareFord, Alice FAlice FFordOgasawara, MasashiMasashiOgasawaraSato, AkiAkiSatoIida, AritoshiAritoshiIidaMunot, PinkiPinkiMunotAmbegaonkar, GautamGautamAmbegaonkarPhadke, RahulRahulPhadkeO'Donovan, Dominic GDominic GO'DonovanBuchert, RebeccaRebeccaBuchertGrimmel, MonaMonaGrimmelTöpf, AnaAnaTöpfZaharieva, Irina TIrina TZaharievaBrady, LaurenLaurenBradyHu, YingYingHuLloyd, Thomas EThomas ELloydKlein, Andrea KatharinaAndrea KatharinaKleinSteinlin, MajaMajaSteinlinKuster, AliceAliceKusterMercier, SandraSandraMercierMarcorelles, PascalePascaleMarcorellesPéréon, YannYannPéréonFleurence, EmmanuelleEmmanuelleFleurenceManzur, AdnanAdnanManzurEnnis, SarahSarahEnnisUpstill-Goddard, RosannaRosannaUpstill-GoddardBello, LucaLucaBelloBertolin, CinziaCinziaBertolinPegoraro, ElenaElenaPegoraroSalviati, LeonardoLeonardoSalviatiFrench, Courtney ECourtney EFrenchShatillo, AndriyAndriyShatilloRaymond, F LucyF LucyRaymondHaack, Tobias BTobias BHaackQuijano-Roy, SusanaSusanaQuijano-RoyBöhm, JohannJohannBöhmNelson, IsabelleIsabelleNelsonStojkovic, TanyaTanyaStojkovicEvangelista, TeresinhaTeresinhaEvangelistaStraub, VolkerVolkerStraubRomero, Norma BNorma BRomeroLaporte, JocelynJocelynLaporteMuntoni, FrancescoFrancescoMuntoniNishino, IchizoIchizoNishinoTarnopolsky, Mark AMark ATarnopolskyShorter, JamesJamesShorterBönnemann, Carsten GCarsten GBönnemannTaylor, J PaulJ PaulTaylor2024-10-092024-10-092022-04-28https://boris-portal.unibe.ch/handle/20.500.12422/70472Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.en600 - Technology::610 - Medicine & healtharticle10.48350/1696443548414210.1038/s41467-022-30015-1