Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human DIAPH1 -related cytoskeletopathy
Year: 2019
Type: article
Abstract: 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.
Source: Journal of Medical Genetics
Institutions: Chungnam National University, Biosignal Research Center, Kobe University, Kobe University, National Institutes of Health, Kyoto University, National Institute on Deafness and Other Communication Disorders, Seoul National University, Seoul National University Bundang Hospital, Samsung Medical Center, Sungkyunkwan University, Shinshu University
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Naito Foundation, Seoul National University Bundang Hospital, National Research Foundation, Ministry of Education, Ministry of Health and Welfare, Korea Health Industry Development Institute, National Research Foundation of Korea, Seoul National University Hospital, Japan Society for the Promotion of Science
Awards: Challenge for establishing the criteria of laterality-based diseases in hearing and vision, G1909049578, G2011895895, G2058803952, Mechanism clarification of new symptoms in DFNA1 causing from constitutively active DAI1 mutants, G3946610865, G5008731682, G7597856591, G7731806304, G8101115763
OpenAlex ID: W2970946424