TUBB1 dysfunction in inherited thrombocytopenia causes genome instability

Takayoshi Matsumura*, Ayako Nakamura-Ishizu, Kensuke Takaoka, Hiroaki Maki, Siva S.N.A. Muddineni, Chelsia Q. Wang, Hitoshi Suzushima, Makoto Kawakita, Norio Asou, Masao Matsuoka, Mineo Kurokawa, Motomi Osato, Toshio Suda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Inherited thrombocytopenia is a genetically heterogeneous disease characterized by varying degrees of thrombocytopenia and risk of haematological malignancy, and the genetic cause of many cases remains unknown. We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB1 variant, R251H. TUBB1 encodes the tubulin β-1 chain, a major component of microtubules abundant in megakaryocytes. Variant TUBB1 disrupted the normal assembly of microtubules and impaired proplatelet formation in vitro. In addition, DNA damage response was severely attenuated by loss of TUBB1. We found that the nuclear accumulation of p53 (also termed TP53) and the expression of pro-apoptotic genes triggered by genotoxic stress were blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB1. Thus, we have demonstrated that microtubule dysfunction confers resistance to apoptosis, even in DNA damage-accumulated cells, which explains genome instability in the affected individuals. These studies will lead us to a better understanding of how microtubule dysfunction can contribute to the accumulation of DNA damage, genetic instability and leukaemogenesis.

Original languageEnglish
Pages (from-to)888-902
Number of pages15
JournalBritish Journal of Haematology
Issue number5
StatePublished - Jun 2019
Externally publishedYes


  • TUBB1
  • apoptosis
  • genome instability
  • inherited thrombocytopenia
  • microtubules


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