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Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

Author

Listed:
  • Kellan P. Weston

    (Washington University School of Medicine)

  • Xiaoyi Gao

    (Washington University School of Medicine)

  • Jinghan Zhao

    (Washington University School of Medicine)

  • Kwang-Soo Kim

    (Washington University School of Medicine)

  • Susan E. Maloney

    (Washington University School of Medicine)

  • Jill Gotoff

    (Geisinger Medical Center)

  • Sumit Parikh

    (Neurosciences Institute, Cleveland Clinic)

  • Yen-Chen Leu

    (Academia Sinica)

  • Kuen-Phon Wu

    (Academia Sinica)

  • Marwan Shinawi

    (Washington University School of Medicine)

  • Joshua P. Steimel

    (University of the Pacific)

  • Joseph S. Harrison

    (University of the Pacific)

  • Jason J. Yi

    (Washington University School of Medicine)

Abstract

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.

Suggested Citation

  • Kellan P. Weston & Xiaoyi Gao & Jinghan Zhao & Kwang-Soo Kim & Susan E. Maloney & Jill Gotoff & Sumit Parikh & Yen-Chen Leu & Kuen-Phon Wu & Marwan Shinawi & Joshua P. Steimel & Joseph S. Harrison & J, 2021. "Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27156-0
    DOI: 10.1038/s41467-021-27156-0
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    1. Sidhartha Chaudhury & Monica Berrondo & Brian D Weitzner & Pravin Muthu & Hannah Bergman & Jeffrey J Gray, 2011. "Benchmarking and Analysis of Protein Docking Performance in Rosetta v3.2," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-13, August.
    2. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    3. Ivan Iossifov & Brian J. O’Roak & Stephan J. Sanders & Michael Ronemus & Niklas Krumm & Dan Levy & Holly A. Stessman & Kali T. Witherspoon & Laura Vives & Karynne E. Patterson & Joshua D. Smith & Brya, 2014. "The contribution of de novo coding mutations to autism spectrum disorder," Nature, Nature, vol. 515(7526), pages 216-221, November.
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    1. Zhen Wang & Fengying Fan & Zhihai Li & Fei Ye & Qingxia Wang & Rongchao Gao & Jiaxuan Qiu & Yixin Lv & Min Lin & Wenwen Xu & Cheng Luo & Xuekui Yu, 2024. "Structural insights into the functional mechanism of the ubiquitin ligase E6AP," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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