Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC11338827 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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

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

Nature 20240711 8026

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes<sup>1</sup>. 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 spliceosome<sup>2</sup>. We ...[more]

PMID: 38991538

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Project description:Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

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

Publications

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

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