Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A boy with biallelic frameshift variants in TTC5 and brain malformation resembling tubulinopathies

Journal of Human Genetics volume 66, pages 1189–1192 (2021)Cite this article

Subjects

Abstract

Brain malformations have heterogeneous genetic backgrounds. Tubulinopathies are a wide range of brain malformations caused by variants in tubulin and microtubules-associated genes. Recently biallelic variants in TTC5, also known as stress responsive activator of p300, have been reported in 11 patients from seven families with developmental delay, intellectual disability, and brain malformations. Here, we report compound heterozygous frameshift variants in TTC5 in a Japanese boy who showed severe psychomotor developmental delay and pseudobulbar palsy with growth failure. Brain magnetic resonance imaging showed a simplified gyral pattern and undetectable anterior limb of the internal capsule, suggesting tubulinopathies. Immunoblotting using lymphoblastoid cells derived from the patient showed undetectable TTC5 protein. Ttc5 silencing by RNA interference in Neuro2a cells reduced Tubulin β3 protein level and caused abnormal cell cycle. Our report suggests a possible link between TTC5-related brain malformation and tubulinopathies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Demonacos C, Krstic-Demonacos M, La Thangue NBA. TPR motif cofactor contributes to p300 activity in the p53 response. Mol Cell. 2001;8:71–84.

    Article  CAS  Google Scholar 

  2. Lin Z, Gasic I, Chandrasekaran V, Peters N, Shao S, Mitchison TJ, et al. TTC5 mediates autoregulation of tubulin via mRNA degradation. Science. 2020;367:100–4.

    Article  CAS  Google Scholar 

  3. Gadadhar S, Bodakuntla S, Natarajan K, Janke C. The tubulin code at a glance. J Cell Sci. 2017;130:1347–53.

    CAS  PubMed  Google Scholar 

  4. Laferrière NB, MacRae TH, Brown DL. Tubulin synthesis and assembly in differentiating neurons. Biochem Cell Biol. 1997;75:103–17.

    Article  Google Scholar 

  5. Gonçalves FG, Freddi TAL, Taranath A, Lakshmanan R, Goetti R, Feltrin FS, et al. Tubulinopathies. Top Magn Reson Imaging. 2018;27:395–408.

    Article  Google Scholar 

  6. Rasheed A, Gumus E, Zaki M, Johnson K, Manzoor H, LaForce G, et al. Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability. J Med Genet. 2020. https://doi.org/10.1136/jmedgenet-2020-106849.

  7. Hu H, Kahrizi K, Musante L, Fattahi Z, Herwig R, Hosseini M, et al. Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019;24:1027–39.

    Article  CAS  Google Scholar 

  8. Adams CJ, Pike AC, Maniam S, Sharpe TD, Coutts AS, Knapp S, et al. The p53 cofactor Strap exhibits an unexpected TPR motif and oligonucleotide-binding (OB)-fold structure. Proc Natl Acad Sci USA. 2012;109:3778–83.

    Article  CAS  Google Scholar 

  9. Altonsy MO, Ganguly A, Amrein M, Surmanowicz P, Li SS, Lauzon GJ, et al. Beta3-tubulin is critical for microtubule dynamics, cell cycle regulation, and spontaneous release of microvesicles in human malignant melanoma cells (A375). Int J Mol Sci. 2020;21:E1656.

    Article  Google Scholar 

  10. Masuda T, Wan J, Yerrabelli A, Berlinicke C, Kallman A, Qian J, et al. Off target, but sequence-specific, shRNA-associated trans-activation of promoter reporters in transient transfection assays. PLoS One. 2016;11:e0167867.

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank the patient’s family for participating in this work. We also thank Kyoko Kitagawa, Masumi Tsujimura and Aya Kitamoto for their technical assistance. This work was supported by Grants-in-Aid for Scientific Research (B) (JP20H03641), and (C) (JP 20K08236) from the Japan Society for the Promotion of Science, and grant by the Takeda Science Foundation.

Author information

Authors and Affiliations

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

    Sachiko Miyamoto, Mitsuko Nakashima, Kazushi Aoto, Hiroki Mutoh & Hirotomo Saitsu

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

    Mitsuhiro Kato

  3. Department of Pediatrics, Mie Prefectural General Medical Center, Mie, Japan

    Kenji Sugiyama

  4. Advanced Research Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Ryo Horiguchi

Authors
  1. Sachiko Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuhiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryo Horiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitsuko Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazushi Aoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroki Mutoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirotomo Saitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hirotomo Saitsu.

Ethics declarations

COMPETING interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyamoto, S., Kato, M., Sugiyama, K. et al. A boy with biallelic frameshift variants in TTC5 and brain malformation resembling tubulinopathies. J Hum Genet 66, 1189–1192 (2021). https://doi.org/10.1038/s10038-021-00953-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-021-00953-7

Search

Advanced search

Quick links