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Genes & Genomics

, Volume 35, Issue 2, pp 141–147 | Cite as

Novel mutations of CDKN1C in Japanese patients with Beckwith-Wiedemann syndrome

  • 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 SoejimaEmail author
Research Article

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.

Keywords

Beckwith-Wiedemann syndrome CDKN1C Gene mutation Genomic imprinting 

Notes

Acknowledgments

This study was supported in part by a Grant for Research on Intractable Diseases from the Ministry of Health, Labor, and Welfare, a Grant for Child Health and Development from the National Center for Child Health and Development, and a Grant-in-Aid for Challenging Exploratory Research and a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science.

Conflict of interests

The authors have no conflicts of interest to declare.

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Copyright information

© The Genetics Society of Korea 2013

Authors and Affiliations

  • Hitomi Yatsuki
    • 1
  • Ken Higashimoto
    • 1
  • Kosuke Jozaki
    • 1
  • Kayoko Koide
    • 1
  • Junichiro Okada
    • 2
  • Yoriko Watanabe
    • 2
  • Nobuhiko Okamoto
    • 3
  • Yoshinobu Tsuno
    • 4
  • Yoko Yoshida
    • 5
  • Kazutoshi Ueda
    • 5
  • Kenji Shimizu
    • 6
  • Hirofumi Ohashi
    • 6
  • Tsunehiro Mukai
    • 7
  • Hidenobu Soejima
    • 1
    Email author
  1. 1.Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Faculty of MedicineSaga UniversitySagaJapan
  2. 2.Department of Pediatrics and Child HealthKurume University School of MedicineKurumeJapan
  3. 3.Department of Medical GeneticsOsaka Medical Center and Research Institute for Maternal and Child HealthIzumiJapan
  4. 4.Perinatal Medical Center, Wakayama Medical University HospitalWakayamaJapan
  5. 5.Department of PediatricsKitano Hospital, The Tazuke Kofukai Medical Research InstituteOsakaJapan
  6. 6.Division of Medical GeneticsSaitama Children’s Medical CenterSaitamaJapan
  7. 7.Nishikyushu UniversityKanzakiJapan

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