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A splicing mutation in VPS4B causes dentin dysplasia I
  1. Qi Yang1,
  2. Dong Chen2,
  3. Fu Xiong1,3,
  4. Danna Chen1,
  5. Cuixian Liu1,
  6. Yanhui Liu1,4,
  7. Qiuxia Yu1,
  8. Jun Xiong1,
  9. Jinzhong Liu2,
  10. Kunyang Li2,
  11. Lingfeng Zhao5,
  12. Yuhua Ye1,
  13. Hong Zhou2,
  14. Lingling Hu1,
  15. Zhihui Tian6,
  16. Xuan Shang1,
  17. Leitao Zhang6,
  18. Xiaofeng Wei1,
  19. Wanjun Zhou1,
  20. Dongri Li7,
  21. Wenqing Zhang5,
  22. Xiangmin Xu1,3
  1. 1Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
  2. 2School of Stomatology, Zhengzhou University, Zhengzhou, China
  3. 3Guangdong Genetic Testing Engineering Research Center, Guangzhou, China
  4. 4Department of Prenatal Diagnosis Center, Maternal and Child Health Hospital, Dongguan, China
  5. 5Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
  6. 6Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  7. 7Department of Forensic Science, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
  1. Correspondence to Professor Fu Xiong, Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; xiongfu{at}smu.edu.cn Professor Xiangmin Xu, Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; gzxuxm{at}pub.guangzhou.gd.cn

Abstract

Background Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous.

Methods and results Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2–q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/β-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis.

Conclusions This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/β-catenin signalling pathway.

  • VPS4B
  • Dentin Dysplasia I
  • Splicing Mutation

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