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

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

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Caenorhabditis elegans
Electron Microscopy
Blood Platelets
Intellectual Disability
Deafness
Hypothyroidism
Clustered Regularly Interspaced Short Palindromic Repeats
Genetic Databases
Phenotype
Mutation
Brain
Vacuoles
Infection
Thrombocytopenia
Alleles

ASJC Scopus subject areas

  • General

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Pathogenetic basis of Takenouchi-Kosaki syndrome : Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model. / Uehara, Tomoko; Suzuki, Hidenori; Okamoto, Nobuhiko; Kondoh, Tatsuro; Ahmad, Ayesha; O’Connor, Bridget C.; Yoshina, Sawako; Mitani, Shohei; Kosaki, Kenjiro; Takenouchi, Toshiki.

In: Scientific reports, Vol. 9, No. 1, 4418, 01.12.2019.

Research output: Contribution to journalArticle

Uehara, Tomoko ; Suzuki, Hidenori ; Okamoto, Nobuhiko ; Kondoh, Tatsuro ; Ahmad, Ayesha ; O’Connor, Bridget C. ; Yoshina, Sawako ; Mitani, Shohei ; Kosaki, Kenjiro ; Takenouchi, Toshiki. / Pathogenetic basis of Takenouchi-Kosaki syndrome : Electron microscopy study using platelets in patients and functional studies in a Caenorhabditis elegans model. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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