Pathogenetic basis of Takenouchi-Kosaki syndrome: Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model

Tomoko Uehara, Hidenori Suzuki, Nobuhiko Okamoto, Tatsuro Kondoh, Ayesha Ahmad, Bridget C. O’Connor, Sawako Yoshina, Shohei Mitani, Kenjiro Kosaki, Toshiki Takenouchi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The combined phenotype of thrombocytopenia accompanied by intellectual disability in patients with a de novo heterozygous mutation, i.e., p.Tyr64Cys in CDC42, signifies a clinically recognizable novel syndrome that has been eponymized as “Takenouchi-Kosaki syndrome” (OMIM #616737). In the present study, a detailed phenotypic analysis performed for a total of five patients with Takenouchi-Kosaki syndrome revealed that intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections comprise the cardinal features of this condition. A morphologic analysis of platelets derived from three affected individuals was performed using electron microscopy. The platelets of the three patients were large and spherical in shape. Furthermore, platelet α-granules were decreased, while vacuoles were increased. We further performed a functional analysis of p.Tyr64Cys in CDC42 through CRISPR/Cas9-mediated gene editing in a Caenorhabditis elegans model. This functional analysis suggested that the mutant allele has hypomorphic effects. Takenouchi-Kosaki syndrome is clinically recognizable by the combined phenotype of intellectual disability, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections as well as the identification of a heterozygous de novo mutation in CDC42, i.e., p.Tyr64Cys.

Original languageEnglish
Article number4418
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Pathogenetic basis of Takenouchi-Kosaki syndrome: Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model'. Together they form a unique fingerprint.

  • Cite this