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Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human DIAPH1-related cytoskeletopathy
  1. Bong Jik Kim1,
  2. Takehiko Ueyama2,
  3. Takushi Miyoshi3,4,
  4. Seungmin Lee5,
  5. Jin Hee Han5,
  6. Hye-Rim Park5,
  7. Ah Reum Kim6,
  8. Jayoung Oh5,
  9. Min Young Kim5,
  10. Yong Seok Kang5,
  11. Doo Yi Oh5,
  12. Jiwon Yun7,8,
  13. Sang Mee Hwang7,8,
  14. Nayoung K D Kim6,
  15. Woong-Yang Park6,9,
  16. Shin-ichiro Kitajiri10,
  17. Byung Yoon Choi5,11
  1. 1 Department of Otolaryngology-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea
  2. 2 Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
  3. 3 Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
  4. 4 Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
  5. 5 Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
  6. 6 Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
  7. 7 Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
  8. 8 Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  9. 9 Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Seoul, Korea
  10. 10 Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
  11. 11 Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea
  1. Correspondence to Professor Byung Yoon Choi, Dpt. of otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam 13620, Korea (the Republic of); choiby2010{at}; Professor Takehiko Ueyama; tueyama{at}; Professor Shin-ichiro Kitajiri; kitajiri{at}


Background Diaphanous-related formin 1 (DIA1), which assembles the unbranched actin microfilament and microtubule cytoskeleton, is encoded by DIAPH1. Constitutive activation by the disruption of autoinhibitory interactions between the N-terminal diaphanous inhibitory domain (DID) and C-terminal diaphanous autoregulatory domain (DAD) dysregulates DIA1, resulting in both hearing loss and blood cell abnormalities.

Methods and results Here, we report the first constitutively active mutant in the DID (p.A265S) of humans with only hearing loss and not blood cell abnormality through whole exome sequencing. The previously reported DAD mutants and our DID mutant (p.A265S) shared the finding of diminished autoinhibitory interaction, abnormally upregulated actin polymerisation activity and increased localisations at the plasma membrane. However, the obvious defect in the DIA1-driven assembly of cytoskeleton ‘during cell division’ was only from the DAD mutants, not from p.A265S, which did not show any blood cell abnormality. We also evaluated the five DID mutants in the hydrophobic pocket since four of these five additional mutants were predicted to critically disrupt interaction between the DID and DAD. These additional pathogenic DID mutants revealed varying degrees of defect in the DIA1-driven cytoskeleton assembly, including nearly normal phenotype during cell division as well as obvious impaired autoinhibition, again coinciding with our key observation in DIA1 mutant (p.A265S) in the DID.

Conclusion Here, we report the first mutant in the DID of humans with only hearing loss. The differential cell biological phenotypes of DIA1 during cell division appear to be potential determinants of the clinical severity of DIAPH1-related cytoskeletopathy in humans.

  • clinical genetics
  • molecular genetics
  • cell biology
  • academic medicine

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  • TU, S-iK and BYC are joint senior authors.

  • BJK, TU and TM contributed equally.

  • Contributors BJK, S-iK, TU and BYC conceived and designed the experiments. Experiments were performed by TM, JHH, JO, MYK and TU. Data analyses, including bioinformatics analysis, were performed by BJK, S-iK, TM, JHH, ARK, JO, DYO, NKDK, TU and BYC. Clinical data were analysed by BJK, H-RP, JY, SMH and YSK. Supplementary figures were generated by SL. Administrative assistance was provided by H-RP. The manuscript was written by BJK, S-iK, TM, TU and BYC, and critically reviewed by W-YP. All authors contributed to the final manuscript.

  • Funding This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1A2B2001054 to BYC and 2018R1D1A1B07046159 to BJK.), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant numbers: HI15C1632 and HI17C0952 to BYC), and Seoul National University Bundang Hospital Grant (13-2018-015 to BYC). This research was partly supported by a grant from the Naito Foundation (TU). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval All procedures in this study were approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB-B-1007-105-402). Written informed consent was obtained from all subjects. In the case of minors, written informed consent was obtained from parents or guardians.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.