A novel DSPP mutation is associated with type II dentinogenesis imperfecta in a Chinese family

Abstract

Background: Hereditary defects of tooth dentin are classified into two main groups: dentin dysplasia (DD) (types I and II) and dentinogenesis imperfecta (DGI) (types I, II, and III). Type II DGI is one of the most common tooth defects with an autosomal dominant mode of inheritance. One disease-causing gene, the dentin sialophosphoprotein (DSPP) gene, has been reported for type II DGI.

Methods: In this study, we characterized a four-generation Chinese family with type II DGI that consists of 18 living family members, including 8 affected individuals. Linkage analysis with polymorphic markers D4S1534 and D4S414 that span the DSPP gene showed that the family is linked to DSPP. All five exons and exon-intron boundaries of DSPP were sequenced in members of type II DGI family.

Results: Direct DNA sequence analysis identified a novel mutation (c.49C-->T, p.Pro17Ser) in exon 1 of the DSPP gene. The mutation spot, the Pro17 residue, is the second amino acid of the mature DSP protein, and highly conserved during evolution. The mutation was identified in all affected individuals, but not in normal family members and 100 controls.

Conclusion: These results suggest that mutation p.Pro17Ser causes type II DGI in the Chinese family. This study identifies a novel mutation in the DSPP gene, and expands the spectrum of mutations that cause DGI.

Figure 1

Pedigree structure of a Chinese family affected with type II DGI. Affected males and females are indicated by filled squares and circles, respectively. Normal individuals are shown as empty symbols. The proband is indicated by an arrow. Linkage analysis was performed with two polymorphic microsatellite markers, D4S414 and D4S1534 linked to the DSPP gene. Genotypic results are shown under each symbol. Note that haplotype 1–4 co-segregates with affected individuals, suggesting that the disease-causing gene in the family is linked to DSPP.

Figure 2

a-b. Oral photographs from the affected individual (IV:2 in Fig. 1). The primary teeth showed shade of brown and almost complete attrition of the enmel layer. c. Panorex radiographs from the affected individual (IV:2 in Fig. 1).

Figure 3

Identification of a novel mutation, g.49C→T/(Pro17Ser), in the DSPP gene in the Chinese family with type II DGI. a. DNA sequences for a normal family member (upper panel) and the proband III-1 (lower panel). The sequence of codon 17 where the mutation occurs is boxed. The C to T change in the proband results in the substitution of a proline residue by a serine residue in the DSP protein. The predicted signal peptide domain covers the first 15 amino acids, MKIITYFCIWAVAWA. The mature protein starts with the next isoleucine (I) residue. b. The alignment of amino acids in the N-terminal domain of DSPP from homo sapiens, sus scrofa, bos taurus, mus musculus, and rattus norvegious revealed that the Pro17 residue was highly conserved during evolution.

Figure 4

Mutation Pro17Ser of the DSPP gene co-segregated with type II DGI in the family. N, normal phenotype; P, affected phenotype; marker, molecular size standard. The lanes are labelled with the unique identification number for each individual in the Chinese family as in Fig. 1. The g.49C>T/Pro17Ser mutation disrupts a BsrI restriction site. The wild type PCR product can be cut by BsrI, yielding two DNA fragments of 268 bp and 200 bp. The PCR fragment containing mutation Pro17Ser cannot be cut by the enzyme, resulting in only one DNA fragment of 468 bp. All affected individuals in the family are heterozygous for the Pro17Ser mutation (three fragments: 468 bp, 268 bp and 200 bp). Normal family members display two 268 bp and 200 bp bands.