De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.

Quinodoz, M.; Rodenburg, K.; Cvackova, Z.; Kaminska, K.; de Bruijn, SE.; Iglesias-Romero, AB.; Boonen, EGM.; Ullah, M.; Zomer, N.; Folcher, M.; Bijon, J.; Holtes, LK.; Tsang, SH.; Corradi, Z.; Freund, KB.; Shliaga, S.; Panneman, DM.; Hitti-Malin, RJ.; Ali, M.; AlTalbishi, A.; Andreasson, S.; Ansari, G.; Arno, G.; Astuti, GDN.; Ayuso, C.; Ayyagari, R.; Banfi, S.; Banin, E.; Barakat, TS.; Barboni, MTS.; Bauwens, M.; Ben-Yosef, T.; Bernard, V.; Birch, DG.; Biswas, P.; Blanco-Kelly, F.; Bocquet, B.; Boon, CJF.; Branham, K.; Bremond-Gignac, D.; Britten-Jones, AC.; Bujakowska, KM.; Burin des Roziers, C.; Cadena, EL.; Calzetti, G.; Cancellieri, F.; Cattaneo, L.; Chadderton, N.; Charbel Issa, P.; Coutinho-Santos, L.; Daiger, SP.; De Baere, E.; De Bruyne, M.; de la Cerda, B.; De Roach, JN.; De Zaeytijd, J.; Derks, R.; Dhaenens, CM.; Dudakova, L.; Duncan, JL.; Farrar, GJ.; Feltgen, N.; Fenner, BJ.; Fernandez-Caballero, L.; Ferraz Sallum, JM.; Gana, S.; Garanto, A.; Gardner, JC.; Gilissen, C.; Gonzalez-Duarte, R.; Goto, K.; Griffiths-Jones, S.; Haack, TB.; Haer-Wigman, L.; Hardcastle, AJ.; Hayashi, T.; Heon, E.; Hoefsloot, LH.; Hoischen, A.; Holtan, JP.; Hoyng, CB.; Ibanez MBB, 4th.; Inglehearn, CF.; Iwata, T.; Jensson, BO.; Jones, K.; Kalatzis, V.; Kamakari, S.; Karali, M.; Kellner, U.; Klaver, CCW.; Knezy, K.; Koenekoop, RK.; Kohl, S.; Kominami, T.; Kuhlewein, L.; Lamey, TM.; Leibu, R.; Leroy, BP.; Liskova, P.; Lopez, I.; Lopez-Rodriguez, VRJ.; Mahieu, Q.; Mahroo, OA.; Manes, G.; Mansard, L.; Martin-Gutierrez, MP.; Martins, N.; Mauring, L.; McKibbin, M.; McLaren, TL.; Meunier, I.; Michaelides, M.; Millan, JM.; Mizobuchi, K.; Mukherjee, R.; Nagy, ZZ.; Neveling, K.; Oldak, M.; Oorsprong, M.; Pan, Y.; Papachristou, A.; Percesepe, A.; Pfau, M.; Pierce, EA.; Place, E.; Ramesar, R.; Ramond, F.; Rasquin, FA.; Rice, GI.; Roberts, L.; Rodriguez-Hidalgo, M.; Ruiz-Ederra, J.; Sabir, AH.; Sajiki, AF.; Sanchez-Barbero, AI.; Sarma, AS.; Sangermano, R.; Santos, CM.; Scarpato, M.; Scholl, HPN.; Sharon, D.; Signorini, SG.; Simonelli, F.; Sousa, AB.; Stefaniotou, M.; Stefansson, K.; Stingl, K.; Suga, A.; Sulem, P.; Sullivan, LS.; Szabo, V.; Szaflik, JP.; Taurina, G.; Thiadens, AAHJ.; Toomes, C.; Tran, VH.; Tsilimbaris, MK.; Tsoka, P.; Vaclavik, V.; Vajter, M.; Valeina, S.; Valente, EM.; Valentine, C.; Valero, R.; Valleix, S.; van Aerschot, J.; van den Born, LI.; Van Heetvelde, M.; Verhoeven, VJM.; Vincent, AL.; Webster, AR.; Whelan, L.; Wissinger, B.; Yioti, GG.; Yoshitake, K.; Zenteno, JC.; Zeuli, R.; Zuleger, T.; Landau, C.; Jacob, AI.; Lin, S.; Cremers, FPM.; Lee, W.; Ellingford, JM.; Stanek, D.; Roosing, S.; Rivolta, C.

De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.

All Authors

Quinodoz, M.

Rodenburg, K.

Cvackova, Z.

Kaminska, K.

de Bruijn, SE.

Iglesias-Romero, AB.

Boonen, EGM.

Ullah, M.

Zomer, N.

Folcher, M.

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LTHT Author

McKibbin, Martin
Mukherjee, Rajarshi

LTHT Department

Head & Neck
Ophthalmology

Publication Date

2026

Item Type

Journal Article

Subject

RETINITIS PIGMENTOSA , GENETICS

Abstract

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, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration. Copyright © 2026. The Author(s).