A novel mutation of adenomatous polyposis coli (APC) gene results in the formation of supernumerary teeth

Abstract

Supernumerary teeth are teeth that are present in addition to normal teeth. Although several hypotheses and some molecular signalling pathways explain the formation of supernumerary teeth, but their exact disease pathogenesis is unknown. To study the molecular mechanisms of supernumerary tooth-related syndrome (Gardner syndrome), a deeper understanding of the aetiology of supernumerary teeth and the associated syndrome is needed, with the goal of inhibiting disease inheritance via prenatal diagnosis. We recruited a Chinese family with Gardner syndrome. Haematoxylin and eosin staining of supernumerary teeth and colonic polyp lesion biopsies revealed that these patients exhibited significant pathological characteristics. APC gene mutations were detected by PCR and direct sequencing. We revealed the pathological pathway involved in human supernumerary tooth development and the mouse tooth germ development expression profile by RNA sequencing (RNA-seq). Sequencing analysis revealed that an APC gene mutation in exon 15, namely 4292-4293-Del GA, caused Gardner syndrome in this family. This mutation not only initiated the various manifestations typical of Gardner syndrome but also resulted in odontoma and supernumerary teeth in this case. Furthermore, RNA-seq analysis of human supernumerary teeth suggests that the APC gene is the key gene involved in the development of supernumerary teeth in humans. The mouse tooth germ development expression profile shows that the APC gene plays an important role in tooth germ development. We identified a new mutation in the APC gene that results in supernumerary teeth in association with Gardner syndrome. This information may shed light on the molecular pathogenesis of supernumerary teeth. Gene-based diagnosis and gene therapy for supernumerary teeth may become available in the future, and our study provides a high-resolution reference for treating other syndromes associated with supernumerary teeth.

Keywords: adenomatous polyposis coli (APC); gardner syndrome; mutation; supernumerary teeth.

Figure 1

Pedigree of the Gardner syndrome family. (A) Pedigree of the proband's family from Shanghai, China. Arrow indicates proband III‐1, a 15‐year‐old male; (B) Oral examination of the Gardner syndrome family; (C) Enteroscopy examination of the Gardner syndrome family.

Figure 2

Adenomatous polyposis coli (APC) gene structure and partial DNA sequences of exon 15 of the APC gene from the proband's family. (A) APC gene structure; (B) The arrow indicates the position of the APC heterozygous mutation 4292‐4293‐Del GA associated with supernumerary teeth in Gardner syndrome patients.

Figure 3

RNA‐seq analysis. (A) Heatmap showing the relative expression of activated genes in the supernumerary teeth patients; (B) GO analysis; (C) KEGG analysis; (D) Interacting proteins for APC gene.

Figure 4

Adenomatous polyposis coli (APC) expression profile in human supernumerary teeth and ICR mouse tooth germ. (A) APC expression levels in human supernumerary teeth and normal teeth based on RNA‐seq; (B) APC expression profile analysis of mouse tooth germ development by RNA‐seq.

Figure 5

Hypothesis for supernumerary teeth pathogenesis.