Tooth Agenesis, Selective, 3

A number sign (#) is used with this entry because of evidence that selective tooth agenesis-3 (STHAG3) is caused by heterozygous mutation in the PAX9 gene (167416) on chromosome 14q13.

For a general phenotypic description and a discussion of genetic heterogeneity of selective tooth agenesis, see STHAG1 (106600).

Clinical Features

Stockton et al. (2000) studied a family segregating a seemingly unique form of oligodontia in an autosomal dominant manner. The affected individuals had normal primary dentition but lacked most permanent molars. Some individuals also lacked maxillary and/or mandibular second premolars as well as mandibular central incisors.

Frazier-Bowers et al. (2002) described a large family with autosomal dominant oligodontia. Affected individuals showed predominantly molar oligodontia but it was not limited to posterior teeth.

Lammi et al. (2003) described a Finnish family segregating autosomal dominant oligodontia with a distinct phenotype involving missing premolars, canines, and incisors in addition to permanent molars, as well as reduced size of both deciduous and permanent teeth. Several second premolars were missing, even though the neighboring first molars were present.

Mostowska et al. (2006) described a 3-generation family with severe autosomal dominant oligodontia. Those affected lacked all permanent molars, second premolars, and mandibular central incisors.

Inheritance

Selective tooth agenesis-3 is an autosomal dominant anomaly (Stockton et al., 2000; Frazier-Bowers et al., 2002).

Mapping

By a genomewide search using microsatellite markers spaced at an average interval of 10 cM throughout the autosomes in a family with oligodontia, Stockton et al. (2000) demonstrated a 2-point lod score of 6.83 at theta = 0.0 with marker D14S288, and the phenotype was localized to an 18.9-cM interval between D14S1060 and D14S276. PAX9 (167416) had previously been mapped to 14q12-q13 by fluorescence in situ hybridization and analysis of somatic cell hybrids. Using radiation hybrid mapping, Stockton et al. (2000) placed PAX9 within the nonrecombinant region for the oligodontia phenotype.

Molecular Genetics

Nieminen et al. (1995) excluded involvement of the MSX1 (142983) and MSX2 (123101) genes in some families with hypodontia involving both second premolars and lateral incisors.

In a family segregating autosomal dominant oligodontia, Stockton et al. (2000) identified heterozygosity for an insertion of a guanine at nucleotide 219 of the PAX9 gene (167416.0001) in affected individuals.

Das et al. (2002) noted that mutations in the PAX9 gene had been found to cause both oligodontia (e.g., 167416.0002) and hypodontia (e.g., 167416.0003). They suggested that the disorders may not be fundamentally different.

Frazier-Bowers et al. (2002) identified a novel insertion mutation in the PAX9 gene (167416.0010) in a large family with autosomal dominant oligodontia.

Lammi et al. (2003) identified a novel missense mutation in the PAX9 gene (167416.0008) in affected members of a Finnish family segregating autosomal dominant oligodontia.

Mostowska et al. (2006) detected a mutation in the PAX9 gene (167416.0012) in all affected individuals in a 3-generation family with severe autosomal dominant oligodontia.

In affected members of a family segregating molar oligodontia, Kapadia et al. (2006) identified a heterozygous missense mutation in the PAX9 gene (167416.0009). Based on functional studies of the mutant and wildtype proteins, Kapadia et al. (2006) suggested that the pathogenesis of oligodontia in this family involves a loss-of-function mechanism that contributes to haploinsufficiency of PAX9.

Genotype/Phenotype Correlations

Kim et al. (2006) analyzed the pattern of tooth agenesis in several kindreds with defined MSX1 and PAX9 mutations. They found that the probability of missing a particular type of tooth is always bilaterally symmetrical, but differences exist between the maxilla and mandible. MSX1-associated tooth agenesis (STHAG1; 106600) typically includes missing maxillary and mandibular second premolars and maxillary first premolars. The most distinguishing feature of MSX1-associated tooth agenesis is the frequent (75%) absence of maxillary first premolars, whereas the most distinguishing feature of PAX9-associated tooth agenesis is the frequent (over 80%) absence of maxillary and mandibular second molars.

Animal Model

Kist et al. (2005) described a hypomorphic Pax9 allele, which they termed Pax9-neo, producing decreased levels of Pax9 wildtype mRNA and showed that this caused oligodontia in mice. Homozygous Pax9 neo/neo mice exhibited hypoplastic or missing lower incisors and third molars. When combined with a Pax9 null allele, the Pax9 neo/null compound mutants developed severe forms of oligodontia. The missing molars were arrested at different developmental stages and posterior molars were consistently arrested at an earlier stage, suggesting that a reduction of Pax9 gene dosage may affect the dental field as a whole. Pax9 neo/neo and neo/null mice also showed defects in enamel formation of the continuously growing incisors, whereas molars exhibited increased attrition and reparative dentin formation.