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De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms

Journal of Human Genetics volume 65, pages 727–734 (2020)Cite this article

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Abstract

The ubiquitin–proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin–proteasome system, leading to diverse neuropsychiatric disorders.

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Fig. 1: Summary of de novo variants in CUL3 and protein interaction with KEAP1 of wild-type and mutant CUL3.

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Acknowledgements

We express our gratitude to all patients and their families for participating in this study. We would also like to thank Ms. M. Sato, N. Watanabe, M Tsujimura, K Shibasaki and A. Kitamoto for their technical assistance. This work was supported by AMED under the grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, JP18kk020501 (to NM); JSPS KAKENHI under the grant numbers JP16H05160 (to HS), JP16K09975 (to MK), JP17H01539 (to NM) and JP19K07977 (to SM); grants from the Ministry of Health, Labor, and Welfare (to NM and MK); and the Takeda Science Foundation (to MN, HS and NM); HUSM Grant-in-Aid from Hamamatsu University School of Medicine.

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Mitsuko Nakashima, Satomi Mitsuhashi & Naomichi Matsumoto

  2. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Mitsuko Nakashima & Hirotomo Saitsu

  3. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    Mitsuhiro Kato

  4. Department of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, Japan

    Masaru Matsukura & Ryutaro Kira

  5. Genetic Department, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia

    Lock-Hock Ngu

  6. Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands

    Klaske D. Lichtenbelt & Koen L. I. van Gassen

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URLs. 3.5KJPN (https://ijgvd.megabank.tohoku.ac.jp/). gnomAD (http://exac.broadinstitute.org). SIFT (http://provean.jcvi.org/index.php). Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/). CADD (http://gnomad.broadinstitute.org/). MutationTaster (http://www.mutationtaster.org/). GERP (http://mendel.stanford.edu/SidowLab/downloads/GERP/index.html). PhastCons (http://compgen.cshl.edu/phast/)

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Nakashima, M., Kato, M., Matsukura, M. et al. De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms. J Hum Genet 65, 727–734 (2020). https://doi.org/10.1038/s10038-020-0758-2

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