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; Beatrice Bocquet; Camiel J F Boon; Kari 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 M 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 Héon; Alexander Hoischen; Josephine P Holtan; Carel B Hoyng; Manuel Benjamin B Ibanez; 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 Millán; Kei Mizobuchi; Rajarshi Mukherjee; Zoltán Zsolt Nagy; Kornelia Neveling; Monika Ołdak; Michiel Oorsprong; Yang Pan; Anastasia Papachristou; Antonio Percesepe; Maximilian Pfau; Eric A 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; Andrew R Webster; Laura Whelan; Bernd Wissinger; Georgia G Yioti; Kazutoshi Yoshitake; Juan C Zenteno; Roberta Zeuli; Theresia Zuleger; Chaim Landau; Allan I Jacob; Frans P M Cremers; Winston Lee; Jamie M Ellingford; David Stanek; Carlo Rivolta; Susanne Roosing

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 AlTalbishiSten 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, Beatrice Bocquet, Camiel J F Boon, Kari 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 M 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 Héon, Alexander Hoischen, Josephine P Holtan, Carel B Hoyng, Manuel Benjamin B Ibanez, 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 Millán, Kei Mizobuchi, Rajarshi Mukherjee, Zoltán Zsolt Nagy, Kornelia Neveling, Monika Ołdak, Michiel Oorsprong, Yang Pan, Anastasia Papachristou, Antonio Percesepe, Maximilian Pfau, Eric A 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, Andrew R Webster, Laura Whelan, Bernd Wissinger, Georgia G Yioti, Kazutoshi Yoshitake, Juan C Zenteno, Roberta Zeuli, Theresia Zuleger, Chaim Landau, Allan I Jacob, Frans P M Cremers, Winston Lee, Jamie M Ellingford, David Stanek, Carlo Rivolta, Susanne Roosing

Division of Evolution, Infection and Genomics

Research output: Preprint/Working paper › Preprint

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
Publisher	medRxiv
DOIs	https://doi.org/10.1101/2025.01.06.24317169
Publication status	Published - 6 Jan 2025

Publication series

Name	medRxiv
Publisher	Cold Spring Harbor Laboratory Press

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10.1101/2025.01.06.24317169Licence: CC BY-NC

Cite this

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., ... Roosing, S. (2025). De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa. (medRxiv). medRxiv. https://doi.org/10.1101/2025.01.06.24317169

@techreport{84586ca7dcc54504b7a54f347a96c125,

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 \textasciitilde{}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 Beatrice Bocquet and Boon, \{Camiel J F\} and Kari Branham and Britten-Jones, \{Alexis Ceecee\} and Bujakowska, \{Kinga M\} and Cadena, \{Elizabeth L\} and Giacomo Calzetti and Francesca Cancellieri and Luca Cattaneo and Issa, \{Peter Charbel\} and Naomi Chadderton and Lu{\'i}sa Coutinho-Santos and Daiger, \{Stephen P\} and \{De Baere\}, Elfride and \{de la Cerda\}, Berta and \{De Roach\}, \{John N\} 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 M 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 H{\'e}on and Alexander Hoischen and Holtan, \{Josephine P\} and Hoyng, \{Carel B\} and Ibanez, \{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 Mill{\'a}n, \{Jos{\'e} M\} and Kei Mizobuchi and Rajarshi Mukherjee and Nagy, \{Zolt{\'a}n Zsolt\} and Kornelia Neveling and Monika O{\l}dak and Michiel Oorsprong and Yang Pan and Anastasia Papachristou and Antonio Percesepe and Maximilian Pfau and Pierce, \{Eric A\} and Emily Place and Raj Ramesar and Rasquin, \{Florence Andr{\'e}e\} and Rice, \{Gillian I\} and Lisa Roberts and Mar{\'i}a Rodr{\'i}guez-Hidalgo and Javier Ruiz-Eddera and Sabir, \{Ataf H\} and Sajiki, \{Ai Fujita\} 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 Signorini, \{Sabrina Giovanna\} and Francesca Simonelli and Sousa, \{Ana Berta\} 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 Webster, \{Andrew R\} and Laura Whelan and Bernd Wissinger and Yioti, \{Georgia G\} and Kazutoshi Yoshitake and Zenteno, \{Juan C\} and Roberta Zeuli and Theresia Zuleger and Chaim Landau and Jacob, \{Allan I\} and Cremers, \{Frans P M\} and Winston Lee and Ellingford, \{Jamie M\} and David Stanek and Carlo Rivolta and Susanne Roosing",

year = "2025",

month = jan,

day = "6",

doi = "10.1101/2025.01.06.24317169",

language = "English",

series = "medRxiv",

publisher = "medRxiv",

address = "United States",

type = "WorkingPaper",

institution = "medRxiv",

}

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, K, Britten-Jones, AC, Bujakowska, KM, Cadena, EL, Calzetti, G, Cancellieri, F, Cattaneo, L, Issa, PC, Chadderton, N, Coutinho-Santos, L, Daiger, SP, De Baere, E, de la Cerda, B, De Roach, JN, 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, Héon, E, Hoischen, A, Holtan, JP, Hoyng, CB, Ibanez, 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, Millán, JM, Mizobuchi, K, Mukherjee, R, Nagy, ZZ, Neveling, K, Ołdak, M, Oorsprong, M, Pan, Y, Papachristou, A, Percesepe, A, Pfau, M, Pierce, EA, Place, E, Ramesar, R, Rasquin, FA, Rice, GI, Roberts, L, Rodríguez-Hidalgo, M, Ruiz-Eddera, J, Sabir, AH, Sajiki, AF, Sánchez-Barbero, AI, Sarma, AS, Sangermano, R, Santos, CM, Scarpato, M, Scholl, HPN, Sharon, D, Signorini, SG, Simonelli, F, Sousa, AB, 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, Webster, AR, Whelan, L, Wissinger, B, Yioti, GG, Yoshitake, K, Zenteno, JC, Zeuli, R, Zuleger, T, Landau, C, Jacob, AI, Cremers, FPM, Lee, W, Ellingford, JM, Stanek, D, Rivolta, C & Roosing, S 2025 'De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa' medRxiv, medRxiv. https://doi.org/10.1101/2025.01.06.24317169

TY - UNPB

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, Beatrice

AU - Boon, Camiel J F

AU - Branham, Kari

AU - Britten-Jones, Alexis Ceecee

AU - Bujakowska, Kinga M

AU - Cadena, Elizabeth L

AU - Calzetti, Giacomo

AU - Cancellieri, Francesca

AU - Cattaneo, Luca

AU - Issa, Peter Charbel

AU - Chadderton, Naomi

AU - Coutinho-Santos, Luísa

AU - Daiger, Stephen P

AU - De Baere, Elfride

AU - de la Cerda, Berta

AU - De Roach, John N

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 M 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 - Héon, Elise

AU - Hoischen, Alexander

AU - Holtan, Josephine P

AU - Hoyng, Carel B

AU - Ibanez, 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 - Millán, José M

AU - Mizobuchi, Kei

AU - Mukherjee, Rajarshi

AU - Nagy, Zoltán Zsolt

AU - Neveling, Kornelia

AU - Ołdak, Monika

AU - Oorsprong, Michiel

AU - Pan, Yang

AU - Papachristou, Anastasia

AU - Percesepe, Antonio

AU - Pfau, Maximilian

AU - Pierce, Eric A

AU - Place, Emily

AU - Ramesar, Raj

AU - Rasquin, Florence Andrée

AU - Rice, Gillian I

AU - Roberts, Lisa

AU - Rodríguez-Hidalgo, María

AU - Ruiz-Eddera, Javier

AU - Sabir, Ataf H

AU - Sajiki, Ai Fujita

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 - Signorini, Sabrina Giovanna

AU - Simonelli, Francesca

AU - Sousa, Ana Berta

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 - Webster, Andrew R

AU - Whelan, Laura

AU - Wissinger, Bernd

AU - Yioti, Georgia G

AU - Yoshitake, Kazutoshi

AU - Zenteno, Juan C

AU - Zeuli, Roberta

AU - Zuleger, Theresia

AU - Landau, Chaim

AU - Jacob, Allan I

AU - Cremers, Frans P M

AU - Lee, Winston

AU - Ellingford, Jamie M

AU - Stanek, David

AU - Rivolta, Carlo

AU - Roosing, Susanne

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 - Preprint

C2 - 39830270

T3 - medRxiv

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

PB - medRxiv

ER -

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

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