Identification of a nonsense mutation in the PAX9 gene in molar oligodontia

Nieminen, Pekka; Arte, Sirpa; Tanner, Dennis D.; Paulín, Lars; Alaluusua, Satu; Thesleff, Irma; Pirinen, Sinikka

doi:10.1038/sj.ejhg.5200715

Cited by 145 publications

(146 citation statements)

References 15 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…Hence, we favor the explanation that the third molars failed to form because they are the last teeth to develop from the dental placode and that the adverse effects of follistatin overexpression earlier in development had resulted in a deficiency of tissue committed to the molar field. This mechanism has been proposed previously as an explanation to the common observation that the most frequently missing teeth in humans are those that develop last in each tooth family (incisors, premolars, and molars; Miles and Grigson, 1990;Nieminen et al, 2001). It is not possible to pinpoint the actual function of the overexpressed follistatin, which led to third molar agenesis, because all epithelial and most mesenchymal cells were probably exposed to the follistatin protein during the entire time of tooth morphogenesis.…”

Section: Overexpression Of Follistatin Inhibits the Formation Of The mentioning

confidence: 96%

Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth

Wang

Suomalainen

Jorgez

et al. 2004

Developmental Dynamics

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Teeth form as ectodermal appendages, and their morphogenesis is regulated by conserved signaling pathways. The shape of the tooth crown results from growth and folding of inner dental epithelium, and the cusp patterning is regulated by transient signaling centers, the enamel knots. Several signal proteins in the transforming growth factor-␤ (TGF␤) superfamily are required for tooth development. Follistatin is an extracellular inhibitor of TGF␤ signaling. To investigate the roles of follistatin during tooth development, we analyzed in detail the expression patterns of follistatin, activin ␤A, as well as Bmp2, Bmp4, and Bmp7 during tooth morphogenesis. We also examined the tooth phenotypes of follistatin knockout mice and of transgenic mice overexpressing follistatin in the epithelium under the keratin 14 (K14) promoter. The folding of the dental epithelium was aberrant in the molars of follistatin knockout mice, and the cusps were shallow with reduced cell proliferation and lack of anteroposterior polarization. The functions of both primary and secondary enamel knots were apparently disturbed. In K14 -follistatin transgenic mice, the molar cusp pattern was also seriously affected (although different from the follistatin knockouts) and the occlusal surfaces of the molars were whorled. Their enamel was prematurely worn. In addition, all of the third molars were missing. Our results indicate that follistatin regulates morphogenesis and shaping of the tooth crown. We propose that finely tuned antagonistic effects between follistatin and TGF␤ superfamily signals are critical for enamel knot formation and function, as well as for patterning of tooth cusps. Developmental Dynamics 231:98 -108, 2004.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Studies on the heredity of dental characteristics in humans have indicated that the variance in many dental traits results from genetic variation. However, the genetic factors that influence commonly occurring dental variants are poorly understood. Paired domain box 9 (PAX9) codes a transcription factor that is important in tooth development. We investigated whether PAX9 polymorphisms are associated with normal variations in tooth agenesis and morphology. The study subjects were 273 Japanese and 223 Korean adults. Single-nucleotide polymorphisms (SNPs) in PAX9 (rs2295222, rs4904155, rs2073244, rs12881240 and rs4904210) were genotyped, and third molar agenesis and mesiodistal and buccolingual diameters were measured. We found that four of the five SNPs were significantly associated with the crown size. However, no SNP was associated with third molar agenesis. In additional analyses on non-metric dental traits, we found significant associations of PAX9 SNPs with shoveling of upper first incisors. In summary, common variants in PAX9 contributed to morphological variation in permanent teeth in humans.

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Identification of a nonsense mutation in the PAX9 gene in molar oligodontia

Cited by 145 publications

References 15 publications

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

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

Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth

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

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