title: A splicing mutation in VPS4B causes dentin dysplasia I.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: School of Stomatology, Zhengzhou University, Zhengzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Guangdong Genetic Testing Engineering Research Center, Guangzhou, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Danna
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Cuixian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Department of Prenatal Diagnosis Center, Maternal and Child Health Hospital, Dongguan, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiong
authors.affiliation: School of Stomatology, Zhengzhou University, Zhengzhou, China.
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Stomatology, Zhengzhou University, Zhengzhou, China.
authors.forename: Kunyang
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Ye
authors.affiliation: School of Stomatology, Zhengzhou University, Zhengzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Leitao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Forensic Science, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Dongri
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Guangdong Genetic Testing Engineering Research Center, Guangzhou, China.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Xu
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D003805:Dentin Dysplasia / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009805:Odontogenesis / Q000235:genetics; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D015027:Zebrafish / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D022821:RNA Splice Sites; D012333:RNA, Messenger; D051176:beta Catenin; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human
keywords: Dentin Dysplasia I; Splicing Mutation; VPS4B