De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

Mathieu Quinodoz; Kim Rodenburg; Zuzana  Cvackova; Karolina  Kaminska; Suzanne E de Bruijn; Ana Belén  Iglesias-Romero; Erica G M  Boonen; Mukhtar  Ullah; Nick  Zomer; Marc  Folcher; Jacques   Bijon; Lara K  Holtes; Stephen H Tsang; Zelia Corradi; K Bailey Freund; Stefanida  Shliaga; Daan M  Panneman; Rebekkah J Hitti-Malin; Manir Ali; Ala'a  AlTalbishi; Sten  Andréasson; Georg  Ansari; Gavin Arno; Galuh D N Astuti; Carmen Ayuso; Radha Ayyagari; Sandro Banfi; Eyal Banin; Mirella T S  Barboni; Miriam Bauwens; Tamar Ben-Yosef; David G Birch; Pooja  Biswas; Fiona  Blanco-Kelly; Béatrice Bocquet; Camiel J F Boon; Kari E Branham; Alexis Ceecee  Britten-Jones; Kinga M Bujakowska; Elizabeth L  Cadena; Giacomo Calzetti; Francesca  Cancellieri; Luca  Cattaneo; Peter Charbel Issa; Naomi  Chadderton; Luísa  Coutinho-Santos; Stephen P  Daiger; Elfride De Baere; Berta  de la Cerda; John N De Roach; Julie de Zaeytijd; Ronny Derks; Claire-Marie Dhaenens; Lubica Dudakova; Jacque L  Duncan; G Jane Farrar; Nicolas  Feltgen; Lidia  Fernández-Caballero; Juliana Maria Ferraz Sallum; Simone  Gana; Alejandro Garanto; Jessica C  Gardner; Christian Gilissen; Kensuke  Goto; Roser  Gonzàlez-Duarte; Sam  Griffiths-Jones; Tobias B  Haack; Lonneke Haer-Wigman; Alison J Hardcastle; Takaaki Hayashi; Elise Heon; Alexander Hoischen; Josephine Prener Holtan; Carel B Hoyng; Manuel Benjamin B  Ibanez 4th; Chris F Inglehearn; Takeshi  Iwata; Kaylie  Jones; Vasiliki  Kalatzis; Smaragda Kamakari; Marianthi Karali; Ulrich Kellner; Krisztina  Knézy; Caroline C W Klaver; Robert K Koenekoop; Susanne Kohl; Taro  Kominami; Laura  Kühlewein; Tina M Lamey; Bart P Leroy; María Pilar  Martín-Gutiérrez; Nelson  Martins; Laura  Mauring; Rina  Leibu; Siying Lin; Petra Liskova; Irma Lopez; Victor R de J  López-Rodríguez; Omar A Mahroo; Gaël Manes; Martin McKibbin; Terri L McLaren; Isabelle Meunier; Michel Michaelides; José M Millan; Kei  Mizobuchi; Rajarshi Mukherjee; Zoltán Zsolt Nagy; Kornelia Neveling; Monika Oldak; Michiel  Oorsprong; Yang  Pan; Anastasia  Papachristou; Antonio  Percesepe; Maximilian  Pfau; Eric Pierce; Emily Place; Raj Ramesar; Florence  Andrée Rasquin; Gillian I  Rice; Lisa Roberts; María  Rodríguez-Hidalgo; Javier  Ruiz-Eddera; Ataf H  Sabir; Ai  Fujita Sajiki; Ana Isabel  Sánchez-Barbero; Asodu Sandeep  Sarma; Riccardo Sangermano; Cristina M  Santos; Margherita  Scarpato; Hendrik P N Scholl; Dror Sharon; Sabrina  Giovanna Signorini; Francesca Simonelli; Ana  Berta Sousa; Maria  Stefaniotou; Katarina Stingl; Akiko  Suga; Lori S  Sullivan; Viktória  Szabó; Jacek P Szaflik; Gita  Taurina; Carmel Toomes; Viet H  Tran; Miltiadis K  Tsilimbaris; Pavlina  Tsoka; Veronika  Vaclavik; Marie  Vajter; Sandra  Valeina; Enza Maria  Valente; Casey  Valentine; Rebeca  Valero; Joseph  van Aerschot; L Ingeborgh van den Born; Susanne Roosing; Carlo Rivolta; David  Stanek; Jamie M Ellingford; Winston Lee; Frans P M Cremers; Allan I  Jacob; Chaim   Landau; Theresia  Zuleger; Roberta  Zeuli; Juan C  Zenteno; Kazutoshi  Yoshitake; Georgia G  Yioti; Bernd Wissinger; Laura Whelan; Andrew R Webster

doi:10.1101/2025.01.06.24317169

De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

Mathieu Quinodoz, Kim Rodenburg, Zuzana Cvackova , Karolina Kaminska, Suzanne E de Bruijn, Ana Belén Iglesias-Romero, Erica G M Boonen, Mukhtar Ullah, Nick Zomer, Marc Folcher, Jacques Bijon, Lara K Holtes, Stephen H Tsang, Zelia Corradi, K Bailey Freund, Stefanida Shliaga, Daan M Panneman , Rebekkah J Hitti-Malin, Manir Ali, Ala'a AlTalbishi Sten Andréasson , Georg Ansari, Gavin Arno, Galuh D N Astuti, Carmen Ayuso, Radha Ayyagari, Sandro Banfi, Eyal Banin, Mirella T S Barboni, Miriam Bauwens, Tamar Ben-Yosef, David G Birch, Pooja Biswas, Fiona Blanco-Kelly, Béatrice Bocquet, Camiel J F Boon, Kari E Branham, Alexis Ceecee Britten-Jones , Kinga M Bujakowska, Elizabeth L Cadena, Giacomo Calzetti, Francesca Cancellieri , Luca Cattaneo , Peter Charbel Issa, Naomi Chadderton, Luísa Coutinho-Santos, Stephen P Daiger, Elfride De Baere, Berta de la Cerda, John N De Roach, Julie de Zaeytijd, Ronny Derks, Claire-Marie Dhaenens, Lubica Dudakova, Jacque L Duncan, G Jane Farrar, Nicolas Feltgen, Lidia Fernández-Caballero, Juliana Maria Ferraz Sallum, Simone Gana , Alejandro Garanto, Jessica C Gardner , Christian Gilissen, Kensuke Goto, Roser Gonzàlez-Duarte, Sam Griffiths-Jones, Tobias B Haack, Lonneke Haer-Wigman, Alison J Hardcastle, Takaaki Hayashi, Elise Heon, Alexander Hoischen, Josephine Prener Holtan, Carel B Hoyng, Manuel Benjamin B Ibanez 4th , Chris F Inglehearn, Takeshi Iwata, Kaylie Jones, Vasiliki Kalatzis, Smaragda Kamakari, Marianthi Karali, Ulrich Kellner, Krisztina Knézy, Caroline C W Klaver, Robert K Koenekoop, Susanne Kohl, Taro Kominami , Laura Kühlewein, Tina M Lamey, Bart P Leroy, María Pilar Martín-Gutiérrez, Nelson Martins, Laura Mauring, Rina Leibu, Siying Lin, Petra Liskova, Irma Lopez, Victor R de J López-Rodríguez, Omar A Mahroo, Gaël Manes, Martin McKibbin, Terri L McLaren, Isabelle Meunier, Michel Michaelides, José M Millan, Kei Mizobuchi , Rajarshi Mukherjee, Zoltán Zsolt Nagy, Kornelia Neveling, Monika Oldak, Michiel Oorsprong, Yang Pan, Anastasia Papachristou, Antonio Percesepe, Maximilian Pfau , Eric Pierce, Emily Place, Raj Ramesar, Florence Andrée Rasquin , Gillian I Rice , Lisa Roberts, María Rodríguez-Hidalgo, Javier Ruiz-Eddera, Ataf H Sabir, Ai Fujita Sajiki, Ana Isabel Sánchez-Barbero, Asodu Sandeep Sarma, Riccardo Sangermano, Cristina M Santos, Margherita Scarpato, Hendrik P N Scholl, Dror Sharon, Sabrina Giovanna Signorini, Francesca Simonelli, Ana Berta Sousa, Maria Stefaniotou , Katarina Stingl, Akiko Suga, Lori S Sullivan, Viktória Szabó, Jacek P Szaflik, Gita Taurina, Carmel Toomes, Viet H Tran, Miltiadis K Tsilimbaris, Pavlina Tsoka, Veronika Vaclavik, Marie Vajter, Sandra Valeina, Enza Maria Valente, Casey Valentine, Rebeca Valero , Joseph van Aerschot, L Ingeborgh van den Born, Susanne Roosing, Carlo Rivolta, David Stanek, Jamie M Ellingford, Winston Lee, Frans P M Cremers, Allan I Jacob, Chaim Landau, Theresia Zuleger, Roberta Zeuli , Juan C Zenteno, Kazutoshi Yoshitake, Georgia G Yioti , Bernd Wissinger, Laura Whelan, Andrew R Webster

Research output: Contribution to journal › Article › Research › peer-review

Abstract

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.

Original language	English
Journal	Human Genetics and Genomics Advances
DOIs	https://doi.org/10.1101/2025.01.06.24317169
Publication status	Published - 6 Jan 2025

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10.1101/2025.01.06.24317169

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Quinodoz, M., Rodenburg, K., Cvackova , Z., Kaminska, K., de Bruijn, S. E., Iglesias-Romero, A. B., Boonen, E. G. M., Ullah, M., Zomer, N., Folcher, M., Bijon, J., Holtes, L. K., Tsang, S. H., Corradi, Z., Freund, K. B., Shliaga, S., Panneman , D. M., Hitti-Malin, R. J., Ali, M., ... Webster, A. R. (2025). De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa. Human Genetics and Genomics Advances. https://doi.org/10.1101/2025.01.06.24317169

@article{81909b74cad34c09a8f78901b52b6143,

title = "De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa",

abstract = "The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.",

author = "Mathieu Quinodoz and Kim Rodenburg and Zuzana Cvackova and Karolina Kaminska and {de Bruijn}, {Suzanne E} and Iglesias-Romero, {Ana Bel{\'e}n} and Boonen, {Erica G M} and Mukhtar Ullah and Nick Zomer and Marc Folcher and Jacques Bijon and Holtes, {Lara K} and Tsang, {Stephen H} and Zelia Corradi and Freund, {K Bailey} and Stefanida Shliaga and Panneman, {Daan M} and Hitti-Malin, {Rebekkah J} and Manir Ali and Ala'a AlTalbishi and Sten Andr{\'e}asson and Georg Ansari and Gavin Arno and Astuti, {Galuh D N} and Carmen Ayuso and Radha Ayyagari and Sandro Banfi and Eyal Banin and Barboni, {Mirella T S} and Miriam Bauwens and Tamar Ben-Yosef and Birch, {David G} and Pooja Biswas and Fiona Blanco-Kelly and B{\'e}atrice Bocquet and Boon, {Camiel J F} and Branham, {Kari E} and Britten-Jones, {Alexis Ceecee} and Bujakowska, {Kinga M} and Cadena, {Elizabeth L} and Giacomo Calzetti and Francesca Cancellieri and Luca Cattaneo and {Charbel Issa}, Peter and Naomi Chadderton and Lu{\'i}sa Coutinho-Santos and Daiger, {Stephen P} and {De Baere}, Elfride and {de la Cerda}, Berta and Roach, {John N De} and {de Zaeytijd}, Julie and Ronny Derks and Claire-Marie Dhaenens and Lubica Dudakova and Duncan, {Jacque L} and Farrar, {G Jane} and Nicolas Feltgen and Lidia Fern{\'a}ndez-Caballero and Sallum, {Juliana Maria Ferraz} and Simone Gana and Alejandro Garanto and Gardner, {Jessica C} and Christian Gilissen and Kensuke Goto and Roser Gonz{\`a}lez-Duarte and Sam Griffiths-Jones and Haack, {Tobias B} and Lonneke Haer-Wigman and Hardcastle, {Alison J} and Takaaki Hayashi and Elise Heon and Alexander Hoischen and {Prener Holtan}, Josephine and Hoyng, {Carel B} and {Ibanez 4th}, {Manuel Benjamin B} and Inglehearn, {Chris F} and Takeshi Iwata and Kaylie Jones and Vasiliki Kalatzis and Smaragda Kamakari and Marianthi Karali and Ulrich Kellner and Krisztina Kn{\'e}zy and Klaver, {Caroline C W} and Koenekoop, {Robert K} and Susanne Kohl and Taro Kominami and Laura K{\"u}hlewein and Lamey, {Tina M} and Leroy, {Bart P} and Mart{\'i}n-Guti{\'e}rrez, {Mar{\'i}a Pilar} and Nelson Martins and Laura Mauring and Rina Leibu and Siying Lin and Petra Liskova and Irma Lopez and L{\'o}pez-Rodr{\'i}guez, {Victor R de J} and Mahroo, {Omar A} and Ga{\"e}l Manes and Martin McKibbin and McLaren, {Terri L} and Isabelle Meunier and Michel Michaelides and Millan, {Jos{\'e} M} and Kei Mizobuchi and Rajarshi Mukherjee and Nagy, {Zolt{\'a}n Zsolt} and Kornelia Neveling and Monika Oldak and Michiel Oorsprong and Yang Pan and Anastasia Papachristou and Antonio Percesepe and Maximilian Pfau and Eric Pierce and Emily Place and Raj Ramesar and {Andr{\'e}e Rasquin}, Florence and Rice, {Gillian I} and Lisa Roberts and Mar{\'i}a Rodr{\'i}guez-Hidalgo and Javier Ruiz-Eddera and Sabir, {Ataf H} and {Fujita Sajiki}, Ai and S{\'a}nchez-Barbero, {Ana Isabel} and Sarma, {Asodu Sandeep} and Riccardo Sangermano and Santos, {Cristina M} and Margherita Scarpato and Scholl, {Hendrik P N} and Dror Sharon and {Giovanna Signorini}, Sabrina and Francesca Simonelli and {Berta Sousa}, Ana and Maria Stefaniotou and Katarina Stingl and Akiko Suga and Sullivan, {Lori S} and Vikt{\'o}ria Szab{\'o} and Szaflik, {Jacek P} and Gita Taurina and Carmel Toomes and Tran, {Viet H} and Tsilimbaris, {Miltiadis K} and Pavlina Tsoka and Veronika Vaclavik and Marie Vajter and Sandra Valeina and Valente, {Enza Maria} and Casey Valentine and Rebeca Valero and {van Aerschot}, Joseph and {van den Born}, {L Ingeborgh} and Susanne Roosing and Carlo Rivolta and David Stanek and Ellingford, {Jamie M} and Winston Lee and Cremers, {Frans P M} and Jacob, {Allan I} and Chaim Landau and Theresia Zuleger and Roberta Zeuli and Zenteno, {Juan C} and Kazutoshi Yoshitake and Yioti, {Georgia G} and Bernd Wissinger and Laura Whelan and Webster, {Andrew R}",

year = "2025",

month = jan,

day = "6",

doi = "10.1101/2025.01.06.24317169",

language = "English",

}

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, Andréasson , S, Ansari, G, Arno, G, Astuti, GDN, Ayuso, C, Ayyagari, R, Banfi, S, Banin, E, Barboni, MTS, Bauwens, M, Ben-Yosef, T, Birch, DG, Biswas, P, Blanco-Kelly, F, Bocquet, B, Boon, CJF, Branham, KE, Britten-Jones , AC, Bujakowska, KM, Cadena, EL, Calzetti, G, Cancellieri , F, Cattaneo , L, Charbel Issa, P, Chadderton, N, Coutinho-Santos, L, Daiger, SP, De Baere, E, de la Cerda, B, Roach, JND, de Zaeytijd, J, Derks, R, Dhaenens, C-M, Dudakova, L, Duncan, JL, Farrar, GJ, Feltgen, N, Fernández-Caballero, L, Sallum, JMF, Gana , S, Garanto, A, Gardner , JC, Gilissen, C, Goto, K, Gonzàlez-Duarte, R, Griffiths-Jones, S, Haack, TB, Haer-Wigman, L, Hardcastle, AJ, Hayashi, T, Heon, E, Hoischen, A, Prener Holtan, J, Hoyng, CB, Ibanez 4th , MBB, Inglehearn, CF, Iwata, T, Jones, K, Kalatzis, V, Kamakari, S, Karali, M, Kellner, U, Knézy, K, Klaver, CCW, Koenekoop, RK, Kohl, S, Kominami , T, Kühlewein, L, Lamey, TM, Leroy, BP, Martín-Gutiérrez, MP, Martins, N, Mauring, L, Leibu, R, Lin, S, Liskova, P, Lopez, I, López-Rodríguez, VRDJ, Mahroo, OA, Manes, G, 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, E, Place, E, Ramesar, R, Andrée Rasquin , F, Rice , GI, Roberts, L, Rodríguez-Hidalgo, M, Ruiz-Eddera, J, Sabir, AH, Fujita Sajiki, A, Sánchez-Barbero, AI, Sarma, AS, Sangermano, R, Santos, CM, Scarpato, M, Scholl, HPN, Sharon, D, Giovanna Signorini, S, Simonelli, F, Berta Sousa, A, Stefaniotou , M, Stingl, K, Suga, A, Sullivan, LS, Szabó, V, Szaflik, JP, Taurina, G, Toomes, C, Tran, VH, Tsilimbaris, MK, Tsoka, P, Vaclavik, V, Vajter, M, Valeina, S, Valente, EM, Valentine, C, Valero , R, van Aerschot, J, van den Born, LI, Roosing, S, Rivolta, C, Stanek, D, Ellingford, JM, Lee, W, Cremers, FPM, Jacob, AI, Landau, C, Zuleger, T, Zeuli , R, Zenteno, JC, Yoshitake, K, Yioti , GG, Wissinger, B, Whelan, L & Webster, AR 2025, 'De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa', Human Genetics and Genomics Advances. https://doi.org/10.1101/2025.01.06.24317169

TY - JOUR

T1 - De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

AU - Quinodoz, Mathieu

AU - Rodenburg, Kim

AU - Cvackova , Zuzana

AU - Kaminska, Karolina

AU - de Bruijn, Suzanne E

AU - Iglesias-Romero, Ana Belén

AU - Boonen, Erica G M

AU - Ullah, Mukhtar

AU - Zomer, Nick

AU - Folcher, Marc

AU - Bijon, Jacques

AU - Holtes, Lara K

AU - Tsang, Stephen H

AU - Corradi, Zelia

AU - Freund, K Bailey

AU - Shliaga, Stefanida

AU - Panneman , Daan M

AU - Hitti-Malin, Rebekkah J

AU - Ali, Manir

AU - AlTalbishi , Ala'a

AU - Andréasson , Sten

AU - Ansari, Georg

AU - Arno, Gavin

AU - Astuti, Galuh D N

AU - Ayuso, Carmen

AU - Ayyagari, Radha

AU - Banfi, Sandro

AU - Banin, Eyal

AU - Barboni, Mirella T S

AU - Bauwens, Miriam

AU - Ben-Yosef, Tamar

AU - Birch, David G

AU - Biswas, Pooja

AU - Blanco-Kelly, Fiona

AU - Bocquet, Béatrice

AU - Boon, Camiel J F

AU - Branham, Kari E

AU - Britten-Jones , Alexis Ceecee

AU - Bujakowska, Kinga M

AU - Cadena, Elizabeth L

AU - Calzetti, Giacomo

AU - Cancellieri , Francesca

AU - Cattaneo , Luca

AU - Charbel Issa, Peter

AU - Chadderton, Naomi

AU - Coutinho-Santos, Luísa

AU - Daiger, Stephen P

AU - De Baere, Elfride

AU - de la Cerda, Berta

AU - Roach, John N De

AU - de Zaeytijd, Julie

AU - Derks, Ronny

AU - Dhaenens, Claire-Marie

AU - Dudakova, Lubica

AU - Duncan, Jacque L

AU - Farrar, G Jane

AU - Feltgen, Nicolas

AU - Fernández-Caballero, Lidia

AU - Sallum, Juliana Maria Ferraz

AU - Gana , Simone

AU - Garanto, Alejandro

AU - Gardner , Jessica C

AU - Gilissen, Christian

AU - Goto, Kensuke

AU - Gonzàlez-Duarte, Roser

AU - Griffiths-Jones, Sam

AU - Haack, Tobias B

AU - Haer-Wigman, Lonneke

AU - Hardcastle, Alison J

AU - Hayashi, Takaaki

AU - Heon, Elise

AU - Hoischen, Alexander

AU - Prener Holtan, Josephine

AU - Hoyng, Carel B

AU - Ibanez 4th , Manuel Benjamin B

AU - Inglehearn, Chris F

AU - Iwata, Takeshi

AU - Jones, Kaylie

AU - Kalatzis, Vasiliki

AU - Kamakari, Smaragda

AU - Karali, Marianthi

AU - Kellner, Ulrich

AU - Knézy, Krisztina

AU - Klaver, Caroline C W

AU - Koenekoop, Robert K

AU - Kohl, Susanne

AU - Kominami , Taro

AU - Kühlewein, Laura

AU - Lamey, Tina M

AU - Leroy, Bart P

AU - Martín-Gutiérrez, María Pilar

AU - Martins, Nelson

AU - Mauring, Laura

AU - Leibu, Rina

AU - Lin, Siying

AU - Liskova, Petra

AU - Lopez, Irma

AU - López-Rodríguez, Victor R de J

AU - Mahroo, Omar A

AU - Manes, Gaël

AU - McKibbin, Martin

AU - McLaren, Terri L

AU - Meunier, Isabelle

AU - Michaelides, Michel

AU - Millan, José M

AU - Mizobuchi , Kei

AU - Mukherjee, Rajarshi

AU - Nagy, Zoltán Zsolt

AU - Neveling, Kornelia

AU - Oldak, Monika

AU - Oorsprong, Michiel

AU - Pan, Yang

AU - Papachristou, Anastasia

AU - Percesepe, Antonio

AU - Pfau , Maximilian

AU - Pierce, Eric

AU - Place, Emily

AU - Ramesar, Raj

AU - Andrée Rasquin , Florence

AU - Rice , Gillian I

AU - Roberts, Lisa

AU - Rodríguez-Hidalgo, María

AU - Ruiz-Eddera, Javier

AU - Sabir, Ataf H

AU - Fujita Sajiki, Ai

AU - Sánchez-Barbero, Ana Isabel

AU - Sarma, Asodu Sandeep

AU - Sangermano, Riccardo

AU - Santos, Cristina M

AU - Scarpato, Margherita

AU - Scholl, Hendrik P N

AU - Sharon, Dror

AU - Giovanna Signorini, Sabrina

AU - Simonelli, Francesca

AU - Berta Sousa, Ana

AU - Stefaniotou , Maria

AU - Stingl, Katarina

AU - Suga, Akiko

AU - Sullivan, Lori S

AU - Szabó, Viktória

AU - Szaflik, Jacek P

AU - Taurina, Gita

AU - Toomes, Carmel

AU - Tran, Viet H

AU - Tsilimbaris, Miltiadis K

AU - Tsoka, Pavlina

AU - Vaclavik, Veronika

AU - Vajter, Marie

AU - Valeina, Sandra

AU - Valente, Enza Maria

AU - Valentine, Casey

AU - Valero , Rebeca

AU - van Aerschot, Joseph

AU - van den Born, L Ingeborgh

AU - Roosing, Susanne

AU - Rivolta, Carlo

AU - Stanek, David

AU - Ellingford, Jamie M

AU - Lee, Winston

AU - Cremers, Frans P M

AU - Jacob, Allan I

AU - Landau, Chaim

AU - Zuleger, Theresia

AU - Zeuli , Roberta

AU - Zenteno, Juan C

AU - Yoshitake, Kazutoshi

AU - Yioti , Georgia G

AU - Wissinger, Bernd

AU - Whelan, Laura

AU - Webster, Andrew R

PY - 2025/1/6

Y1 - 2025/1/6

N2 - The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.

AB - The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5' stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2, where different variants underlie neurodevelopmental disorder and RP.

U2 - 10.1101/2025.01.06.24317169

DO - 10.1101/2025.01.06.24317169

M3 - Article

C2 - 39830270

SN - 2666-2477

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

ER -

De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

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