Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia

Abstract

We recently identified a frame-shift mutation in the PAX9 gene as the underlying cause for hypodontia involving permanent molar teeth segregating in an autosomal dominant pattern in a single large family (Stockton et al. 2000). Here we report a small nuclear family in which a father and his daughter are affected with severe hypodontia, involving agenesis of all primary and permanent molars, evidently caused by deletion of the entire PAX9 gene. Hemizygosity at the PAX9 locus in the two affected individuals was initially discovered when an informative single nucleotide polymorphism, identified while sequencing the gene for mutations, appeared to demonstrate non-Mendelian inheritance. Fluorescence in situ hybridization (FISH) analysis with a cosmid containing the PAX9 gene yielded a signal on only one chromosome 14 homologue and confirmed the presence of a deletion encompassing the PAX9 locus. Analysis of microsatellite loci in the vicinity of PAX9 delineated one breakpoint of the deletion. These data, in concert with FISH analysis with cosmids encompassing a 199 kb region, indicated that the deletion is between approximately 44 kb and 100 kb. PAX9 is one of two genes, and the only odontogenic gene within the deletion interval, thus supporting the model of haploinsufficiency for PAX9 as the underlying basis for hypodontia.

Growth and specification of the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster

“…These observations are consistent with the view that the distinct roles of PAX6(5a) and PAX6 proteins shown here are not restricted to D. melanogaster. These studies should contribute to our understanding of PAX proteins in dorsal-ventral patterning of the central nervous system, somitogenesis, organogenesis, stem cell biology and human diseases 1,[5][6][7][8][9][10][11][12][13][14][15]45 . Scer\UAS.mg5603 ) and UAS-N ECD (N ECD.Scer\UAS ; two independent insertions on chromosome X and II).…”

“…Mutations in genes encoding Pax proteins not only disrupt organogenesis in fruit flies and mice 6 but also cause congenital disease syndromes in humans [5][6][7][8][9][10] , characterized by loss or hypoplasia of particular organs. Moreover, a growing body of evidence implicates deregulated expression of PAX genes in tissue-specific tumors in humans 5,6,[11][12][13][14][15] .…”

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia

“…Characteristically, when a premolar or molar tooth is missing, all the posterior teeth on the same hemiarch are also absent. 6,8,9,11 Oligodontia of molar teeth was most pronounced in a family with complete deletion of one copy of the PAX9 gene. 11 Our clinical analysis revealed that the pattern of tooth agenesis in the family we describe deviates from PAX9 phenotypes previously reported (Table 4).…”

“…6,8,9,11 Oligodontia of molar teeth was most pronounced in a family with complete deletion of one copy of the PAX9 gene. 11 Our clinical analysis revealed that the pattern of tooth agenesis in the family we describe deviates from PAX9 phenotypes previously reported (Table 4). Several second premolars were missing, even though the neighbouring first molar existed, rather resembling the phenotype seen previously in association with mutations of MSX1.…”

Association of common PAX9 variants with permanent tooth size variation in non-syndromic East Asian populations

“…12,14 In humans, dominant mutations in PAX9 have been identified as a cause of congenital absence of some posterior (and occasionally anterior) teeth. Frame-shift, [15][16][17] insertion, 18,19 missense 18 and non-sense 20,21 mutations, as well as whole-gene deletion, 18,22,23 have been described in families exhibiting hypodontia, primarily with absence of molar teeth. In addition, it has been shown that common polymorphisms in PAX9 are associated with 3rd molar (M3) agenesis.…”