biostudies-literatureQuinodoz MNEI NIH HHSWellcome Trust169-179https://www.ebi.ac.uk/biostudies/studies/S-EPMC12807869biostudies-literatureUnknown58(1)Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF3Nature geneticsDe novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.PMC12807869UG1 EY033292UG1 EY033293P30 EY002162UG1 EY033286R01 EY024698R01 EY030499T32 EY026590K99 EY036930R01 EY018213R01 EY031663R24 EY028758R01 EY030591P30 EY022589R01 EY033770P30 EY019007R24 EY027285R01 EY012910P30 EY014104R01 EY035717U01 EY030580Vaclavik VLin SHaack TBBernard VIglesias-Romero ABSarma ASDudakova LSajiki AFJensson BOZeuli RFarrar GJPapachristou Ade la Cerda BKalatzis VHoltes LKAyyagari RArno GCancellieri FKnezy KLeibu RBiswas PSharon DBurin des Roziers CLamey TMCorradi ZGilissen CMukherjee RRodriguez-Hidalgo MBlanco-Kelly FPfau MValente EMTran VHVajter MScholl HPNVerhoeven VJMBijon JMartins NDe Roach JNSabir AHYioti GGSantos CMHitti-Malin RJHeon EValero RCattaneo LMcLaren TLWebster ARHoefsloot LHFerraz Sallum JMKarali MYoshitake KFeltgen NGriffiths-Jones SFreund KBBremond-Gignac DMahroo OABen-Yosef TLopez IChadderton NOldak MBanin EKellner UHardcastle AJDaiger SPLeroy BPDhaenens CMAlTalbishi ARuiz-Ederra JSullivan LSVincent ALde Bruijn SERamesar RSulem PGardner JCMahieu QUllah MLiskova PMansard LKlaver CCWMauring LRoberts LDe Zaeytijd JKoenekoop RKLee WSignorini SGBranham KShliaga SCremers FPMGonzalez-Duarte RStefansson KBocquet BDe Bruyne MLopez-Rodriguez VRJStingl KAyuso CAndreasson SIbanez MBBBujakowska KMManes GPlace EGana SEllingford JMGoto KRivolta CSimonelli FAstuti GDNvan Aerschot JAnsari GLandau CKominami TMeunier IValleix SStanek DNeveling KRamond FTsoka PBoonen EGMKaminska KStefaniotou MSzabo VJacob AISousa ABTsang SHCadena ELRoosing SFolcher MDe Baere ERasquin FABirch DGHoischen ANagy ZZKuhlewein LCvackova ZJones KThiadens AAHJSanchez-Barbero AIBanfi SSzaflik JPZuleger TKamakari SMillan JMQuinodoz MFernandez-Caballero LSuga AValentine CBoon CJFMcKibbin MZenteno JCToomes CCalzetti GHayashi TBritten-Jones ACvan den Born LIVan Heetvelde MBarakat TSValeina SPanneman DMDuncan JLPercesepe AHoyng CBCharbel Issa PZomer NCoutinho-Santos LTaurina GGaranto AHaer-Wigman LMizobuchi KPan YRice GISangermano RWissinger BPierce EAAli MMichaelides MFenner BJOorsprong MIwata TBarboni MTSDerks RScarpato MKohl SHoltan JPBauwens MTsilimbaris MKWhelan LMartin-Gutierrez MPRodenburg KInglehearn CFfalseDe novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF32026-01-01T00:00:00Z2026 Jan2026-06-06T14:01:37.392Z2026-05-31T03:10:16.21ZS-EPMC128078694151398210.1038/s41588-025-02451-4