Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome |
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Authors: | Hitomi Yatsuki Ken Higashimoto Kosuke Jozaki Kayoko Koide Junichiro Okada Yoriko Watanabe Nobuhiko Okamoto Yoshinobu Tsuno Yoko Yoshida Kazutoshi Ueda Kenji Shimizu Hirofumi Ohashi Tsunehiro Mukai Hidenobu Soejima |
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Affiliation: | 1. Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, 849-8501, Japan 2. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, 830-0011, Japan 3. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, 594-1101, Japan 4. Perinatal Medical Center, Wakayama Medical University Hospital, Wakayama, 641-8510, Japan 5. Department of Pediatrics, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, 530-8480, Japan 6. Division of Medical Genetics, Saitama Children’s Medical Center, Saitama, 339-8551, Japan 7. Nishikyushu University, Kanzaki, 842-8585, Japan
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Abstract: | Beckwith-Wiedemann syndrome (BWS) is an imprinting-related human disease that is characterized by macrosomia, macroglossia, abdominal wall defects, and variable minor features. BWS is caused by several genetic/epigenetic alterations, such as loss of methylation at KvDMR1, gain of methylation at H19-DMR, paternal uniparental disomy of chromosome 11, CDKN1C mutations, and structural abnormalities of chromosome 11. CDKN1C is an imprinted gene with maternal preferential expression, encoding for a cyclin-dependent kinase (CDK) inhibitor. Mutations in CDKN1C are found in 40 % of familial BWS cases with dominant maternal transmission and in ~5 % of sporadic cases. In this study, we searched for CDKN1C mutations in 37 BWS cases that had no evidence for other alterations. We found five mutations—four novel and one known—from a total of six patients. Four were maternally inherited and one was a de novo mutation. Two frame-shift mutations and one nonsense mutation abolished the QT domain, containing a PCNA-binding domain and a nuclear localization signal. Two missense mutations occurred in the CDK inhibitory domain, diminishing its inhibitory function. The above-mentioned mutations were predicted by in silico analysis to lead to loss of function; therefore, we strongly suspect that such anomalies are causative in the etiology of BWS. |
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