Mutation inSSUH2Causes Autosomal-Dominant Dentin Dysplasia Type I

Abstract

Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.

Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders

“…39 Recent genetic studies have shown that mutations of collagen type I alpha 1 chain ( COL1A1 ), collagen type I alpha 2 chain ( COL1A2 ), DSPP , secreted modular calcium-binding protein 2 ( SMOC2 ), vacuolar protein sorting 4 homologue B ( VPS4B ), and ssu-2 homologue ( SSUH2 ) cause dentin disorders. 39–49 AMBN can enhance reparative dentin formation, which confirms that this protein has an important role in odontoblast differentiation and dentinogenesis. 50 The enamel defects confirm the observations from mouse models and show that human AI is associated with disrupted Ambn function.…”

“…Radiologically, permanent teeth of DD-I have short roots with a crescent-shaped pulpal remnant parallel to the cemento-enamel junction in the permanent dentition and total pulpal obliteration in the dentition. 48,49 There are usually numerous periapical radiolucencies in non-carious teeth. 48,49 Compared with DD-I, the clinical crowns of affected teeth in our study had similar pulp and root phenotypes, especially the phenotype of periapical radiolucencies in non-carious teeth (Fig.…”

“…18 The hereditary dentin disorders were documented as autosomal-dominant genetic diseases characterized by abnormal dentin structure affecting either the primary or secondary dentitions. 48,49 …”

Dentin dysplasia type I—A dental disease with genetic heterogeneity

“…The results of scanning electron microscopy revealed a significantly reduced number of dentin tubules with smaller diameters (Figure a,b). In addition, we have found two mutant genes: VPS4B (Yang et al., ) in a family from northern China; and SSUH2 in a family from southern China (Xiong et al., ). Different mutations can result in the same disease which is highly suggestive evidence that the disease has genetic heterogeneity.…”

“…To identify essential transcription factors in dental development, specific primers with different junctions at the three mRNA spliceosomes were designed for RT‐PCR amplification. Only the transcript NM_015931.2 including a 1,803 base pair mRNA is highly expressed in human dental pulp stem cells and underjaw tissues (Xiong et al., ). This transcript corresponds to a putative chaperone protein (approximately 39 kDa), which is widely distributed (Reinartz et al., ).…”