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A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome

Abstract

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP-binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation.

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References

  1. 1.

    Takenouchi T, Kosaki R, Niizuma T, Hata K, Kosaki K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A. 2015;167A:2822–5.

    Article  PubMed  Google Scholar 

  2. 2.

    Takenouchi T, Okamoto N, Ida S, Uehara T, Kosaki K. Further evidence of a mutation in CDC42 as a cause of a recognizable syndromic form of thrombocytopenia. Am J Med Genet A. 2016;170A:852–5.

    Article  PubMed  Google Scholar 

  3. 3.

    Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tu S, Wu WJ, Wang J, Cerione RA. Epidermal growth factor-dependent regulation of Cdc42 is mediated by the Src tyrosine kinase. J Biol Chem. 2003;278:49293–300.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Loebel DA, Plageman TF Jr., Tang TL, Jones VJ, Muccioli M, Tam PP. Thyroid bud morphogenesis requires CDC42- and SHROOM3-dependent apical constriction. Biol Open. 2016;5: 130–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Abdul-Manan N, Aghazadeh B, Liu GA, Majumdar A, Ouerfelli O, Siminovitch KA, et al. Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott-Aldrich syndrome’ protein. Nature. 1999;399:379–83.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Yoshida H, Tomiyama Y, Ishikawa J, et al. Integrin-associated protein/CD47 regulates motile activity in human B-cell lines through CDC42. Blood. 2000;96:234–41.

    CAS  PubMed  Google Scholar 

  8. 8.

    Westerberg L, Greicius G, Snapper SB, Aspenström P, Severinson E. Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes. Blood. 2001;98:1086–94.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Grill B, Schrader JW. Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen. Blood. 2002;100:3183–92.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Guo F, Velu CS, et al. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood. 2009;114: 2909–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patient and the family who participated in this study. This work was supported by a grant for the Initiative on Rare and Undiagnosed Diseases in Pediatrics (no. 15gk0110012h0101) from the Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.

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Correspondence to Sumito Dateki.

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Motokawa, M., Watanabe, S., Nakatomi, A. et al. A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome. J Hum Genet 63, 387–390 (2018). https://doi.org/10.1038/s10038-017-0396-5

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