A Novel Splicing Mutation Alters DSPP Transcription and Leads to Dentinogenesis Imperfecta Type II

Jun Zhang,Zuowei Zhang,Yue Liu,Siyang Zhao,Wenqi Du,Xiaojiao Zhang,Jie Liu,Hongyan Wang,Li Jin,Jiucun Wang,Huasheng Xiao,Yanyun Ma,Momiao Xiong

doi:10.1371/journal.pone.0027982

Abstract

Dentinogenesis imperfecta (DGI) type II is an autosomal dominant disease characterized by a serious disorders in teeth. Mutations of dentin sialophosphoprotein (DSPP) gene were revealed to be the causation of DGI type II (DGI-II). In this study, we identified a novel mutation (NG_011595.1:g.8662T>C, c.135+2T>C) lying in the splice donor site of intron 3 of DSPP gene in a Chinese Han DGI-II pedigree. It was found in all affected subjects but not in unaffected ones or other unrelated healthy controls. The function of the mutant DSPP gene, which was predicted online and subsequently confirmed by in vitro splicing analysis, was the loss of splicing of intron 3, leading to the extended length of DSPP mRNA. For the first time, the functional non-splicing of intron was revealed in a novel DSPP mutation and was considered as the causation of DGI-II. It was also indicated that splicing was of key importance to the function of DSPP and this splice donor site might be a sensitive mutation hot spot. Our findings combined with other reports would facilitate the genetic diagnosis of DGI-II, shed light on its gene therapy and help to finally conquer human diseases.

Highlights

Dentinogenesis imperfecta (DGI), a kind of hereditary dentin defect, causes the teeth of the patients discolored, translucent and even weaker than normal
DGI type III (DGI-III), which was first found in three isolated pedigrees in the United States in 1957, is considered as a more severe form of DGI-II [1]
We identified a pedigree with severe DGI-II in Shaanxi, China

Summary

Introduction

Dentinogenesis imperfecta (DGI), a kind of hereditary dentin defect, causes the teeth of the patients discolored, translucent and even weaker than normal. Mutations in the DSPP gene have been revealed and reported to be the principal cause of DGI type II and type III [1,2,3,4]. Most of these mutations were just reported in DGI affected individuals by sequence analysis, but not further functionally confirmed.

Results

Conclusion