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KMID : 0381120130350020141
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Genes and Genomics
2013 Volume.35 No. 2 p.141 ~ p.147
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Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome
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Yatsuki Hitomi
Higashimoto Ken
Jozaki Kosuke
Koide Kayoko
Okada Junichiro
Watanabe Yoriko
Okamoto Nobuhiko
Tsuno Yoshinobu
Yoshida Yoko
Ueda Kazutoshi
Shimizu Kenji
Ohashi Hirofumi
Mukai Tsunehiro
Soejima Hidenobu
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Abstract
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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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KEYWORD
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Beckwith-Wiedemann syndrome, CDKN1C, Gene mutation, Genomic imprinting
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