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Sci Rep. 2019 Mar 14;9(1):4418. doi: 10.1038/s41598-019-40988-7.

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

Author information

1
Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
2
Division of Morphological and Biomolecular Research, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
3
Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.
4
Misakaenosono Mutsumi Developmental, Medical, and Welfare Center, Isahaya, Japan.
5
Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
6
Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
7
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. toshiki.take@keio.jp.

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.

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