m+Medelevator.RU
← Поиск публикаций
Nature · 2024

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

СтатьяПоддержка NIH: внешняя программаПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

Chen Yuyang, Dawes Ruebena, Kim Hyung Chul, Ljungdahl Alicia, Stenton Sarah L, Walker Susan, Lord Jenny, Lemire Gabrielle, Martin-Geary Alexandra C, Ganesh Vijay S, Ma Jialan, Ellingford Jamie M, Delage Erwan, D'Souza Elston N, Dong Shan, Adams David R, Allan Kirsten, Bakshi Madhura, Baldwin Erin E, Berger Seth I, Bernstein Jonathan A, Bhatnagar Ishita, Blair Ed, Brown Natasha J, Burrage Lindsay C, Chapman Kimberly, Coman David J, Compton Alison G, Cunningham Chloe A, D'Souza Precilla, Danecek Petr, Délot Emmanuèle C, Dias Kerith-Rae, Elias Ellen R, Elmslie Frances, Evans Care-Anne, Ewans Lisa, Ezell Kimberly, Fraser Jamie L, Gallacher Lyndon, Genetti Casie A, Goriely Anne, Grant Christina L, Haack Tobias, Higgs Jenny E, Hinch Anjali G, Hurles Matthew E, Kuechler Alma, Lachlan Katherine L, Lalani Seema R, Lecoquierre François, Leitão Elsa, Fevre Anna Le, Leventer Richard J, Liebelt Jan E, Lindsay Sarah, Lockhart Paul J, Ma Alan S, Macnamara Ellen F, Mansour Sahar, Maurer Taylor M, Mendez Hector R, Metcalfe Kay, Montgomery Stephen B, Moosajee Mariya, Nassogne Marie-Cécile, Neumann Serena, O'Donoghue Michael, O'Leary Melanie, Palmer Elizabeth E, Pattani Nikhil, Phillips John, Pitsava Georgia, Pysar Ryan, Rehm Heidi L, Reuter Chloe M, Revencu Nicole, Riess Angelika, Rius Rocio, Rodan Lance, Roscioli Tony, Rosenfeld Jill A, Sachdev Rani, Shaw-Smith Charles J, Simons Cas, Sisodiya Sanjay M, Snell Penny, St Clair Laura, Stark Zornitza, Stewart Helen S, Tan Tiong Yang, Tan Natalie B, Temple Suzanna E L, Thorburn David R, Tifft Cynthia J, Uebergang Eloise, VanNoy Grace E, Vasudevan Pradeep, Vilain Eric, Viskochil David H, Wedd Laura, Wheeler Matthew T, White Susan M, Wojcik Monica, Wolfe Lynne A, Wolfenson Zoe, Wright Caroline F, Xiao Changrui, Zocche David, Rubenstein John L, Markenscoff-Papadimitriou Eirene, Fica Sebastian M, Baralle Diana, Depienne Christel, MacArthur Daniel G, Howson Joanna M M, Sanders Stephan J, O'Donnell-Luria Anne, Whiffin Nicola

Аннотация

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты