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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Publication ,  Journal Article
Li, D; Wang, Q; Bayat, A; Battig, MR; Zhou, Y; Bosch, DG; van Haaften, G; Granger, L; Petersen, AK; Pérez-Jurado, LA; Aznar-Laín, G; Aneja, A ...
Published in: J Clin Invest
January 2, 2024

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 7 recurrent variants in 30 individuals) and 6 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 (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were 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 reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Duke Scholars

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

January 2, 2024

Volume

134

Issue

1

Location

United States

Related Subject Headings

  • Spliceosomes
  • RNA Splicing Factors
  • RNA Splicing
  • Nuclear Proteins
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Immunology
  • Humans
  • Gene Regulatory Networks
  • DNA Repair Enzymes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Li, D., Wang, Q., Bayat, A., Battig, M. R., Zhou, Y., Bosch, D. G., … Hakonarson, H. (2024). Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. J Clin Invest, 134(1). https://doi.org/10.1172/JCI171235
Li, Dong, Qin Wang, Allan Bayat, Mark R. Battig, Yijing Zhou, Daniëlle Gm Bosch, Gijs van Haaften, et al. “Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.J Clin Invest 134, no. 1 (January 2, 2024). https://doi.org/10.1172/JCI171235.
Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, et al. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. J Clin Invest. 2024 Jan 2;134(1).
Li, Dong, et al. “Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.J Clin Invest, vol. 134, no. 1, Jan. 2024. Pubmed, doi:10.1172/JCI171235.
Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O’Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh T-C, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel A-L, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, Hakonarson H. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features. J Clin Invest. 2024 Jan 2;134(1).

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

January 2, 2024

Volume

134

Issue

1

Location

United States

Related Subject Headings

  • Spliceosomes
  • RNA Splicing Factors
  • RNA Splicing
  • Nuclear Proteins
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Immunology
  • Humans
  • Gene Regulatory Networks
  • DNA Repair Enzymes