Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F24%3A10471086" target="_blank" >RIV/00216208:11130/24:10471086 - isvavai.cz</a>
Alternative codes found
RIV/00064203:_____/24:10471086
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=fNGLi1DWmQ" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=fNGLi1DWmQ</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1172/JCI171235" target="_blank" >10.1172/JCI171235</a>
Alternative languages
Result language
angličtina
Original language name
Spliceosome malfunction causes neurodevelopmental disorders with overlapping features
Original language description
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30101 - Human genetics
Result continuities
Project
<a href="/en/project/NU22-07-00165" target="_blank" >NU22-07-00165: Identification and analysis of genes and genetic defects causing rare neurodevelopmental disorders in children</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Clinical Investigation
ISSN
0021-9738
e-ISSN
1558-8238
Volume of the periodical
134
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
17
Pages from-to
e171235
UT code for WoS article
001171162100005
EID of the result in the Scopus database
2-s2.0-85181539861