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.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
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.
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.
Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.
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.
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.
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.
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.
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.
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.
Guo F, Velu CS, et al. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood. 2009;114: 2909–16.
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s10038-017-0396-5
This article is cited by
-
KLHL23 and RhoGDI coordinate CDC42 inactivation ensuring membrane homeostasis
Nature Chemical Biology (2025)
-
Splenectomy as an effective treatment for macrothrombocytopenia in Takenouchi-Kosaki syndrome
International Journal of Hematology (2023)
-
Novel Genetic Discoveries in Primary Immunodeficiency Disorders
Clinical Reviews in Allergy & Immunology (2022)
-
Macrothrombocytopenia of Takenouchi-Kosaki syndrome is ameliorated by CDC42 specific- and lipidation inhibitors in MEG-01 cells
Scientific Reports (2021)
-
RHO GTPases: from new partners to complex immune syndromes
Nature Reviews Immunology (2021)
