Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia

Kist, Ralf; Watson, Michelle; Cairns, Paul; Miles, Colin; Reid, Donald J.; Peters, Heiko

doi:10.1093/hmg/ddi388

Cited by 80 publications

(88 citation statements)

References 40 publications

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“…In this study, the G16A (G6R) mutation shows a surprisingly mild and atypical phenotype where first and second molars were unaffected. While studies in mice have clearly shown that PAX9 dosage is critical for tooth morphogenesis and differentiation [Kist et al, 2005], the study of naturally occurring mutations in humans affords a unique opportunity to relate different tooth agenesis phenotypes to gene function.…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

Wang¹,

Wu²,

Wu³

et al. 2008

Cells Tissues Organs

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The paired-domain transcription factor PAX9 plays a critical role in tooth development, as heterozygous mutations in PAX9 have been shown to be associated with human tooth agenesis. In this study, we report 2 novel missense mutations, gly6arg (G6R) and ser43lys (S43K), in the paired domain of PAX9 in Chinese patients with varying degrees of nonsyndromic tooth agenesis. Excluding third molars, the individual with the G6R mutation was missing 2 mandibular incisors and a maxillary premolar, while the phenotype of individuals with the S43K mutation consisted of peg-shaped upper lateral incisors and missing molars, premolars and canines. As these 2 mutations occur at highly conserved amino acids in the PAX gene family and between different species, we further analyzed the effects of the mutations on the function of the resulting proteins. Immunofluorescence and immunoblotting studies showed that the mutations did not alter nuclear localization in mammalian cells. Gel shift and super shift assays indicate that both mutant proteins bound DNA at a lower level than the normal protein, with G6R having a greater affinity for DNA than S43K. Likewise, the G6R protein was able to transcriptionally activate a Bmp4 promoter construct to a greater extent than S43K. Our finding that the severity of tooth agenesis in the patients was correlated to the DNA-binding capacity of the mutated PAX9 9proteins supports the hypothesis that DNA binding is responsible for the genetic defect.

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Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

Wang¹,

Wu²,

Wu³

et al. 2008

Cells Tissues Organs

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show abstract

“…It is tempting to speculate that Pro carriers, harboring a slightly altered structure of the transcription factor PAX9, might have normal first and second molars dentition because of the putative overlapping expression of MSX1 and PAX9 during tooth development (18). Nevertheless, they might fail to form third molars beyond the bud stage, because the maintenance of BMP4 expression (or another signal essential to the next round of tooth formation) in prospective third molars may depend predominantly (or exclusively) on PAX9 expression and͞or physical interaction with this transcription factor (55).…”

Section: Could the Ala240pro Mutation Be Advantageous In Humans?mentioning

confidence: 99%

Natural selection and molecular evolution in primatePAX9gene, a major determinant of tooth development

Pereira

Salzano

Mostowska

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Large differences in relation to dental size, number, and morphology among and within modern human populations and between modern humans and other primate species have been observed. Molecular studies have demonstrated that tooth development is under strict genetic control, but, the genetic basis of primate tooth variation remains unknown. The PAX9 gene, which codes for a paired domain-containing transcription factor that plays an essential role in the development of mammal dentition, has been associated with selective tooth agenesis in humans and mice, which mainly involves the posterior teeth. To determine whether this gene is polymorphic in humans, we sequenced Ϸ2.1 kb of the entire four-exon region (exons 1, 2, 3 and 4; 1,026 bp) and exon-intron (1.1 kb) boundaries of 86 individuals sampled from Asian, European, and Native American populations. We provided evidence that human PAX9 polymorphisms are limited to exon 3 only and furnished details about the distribution of a mutation there in 350 Polish subjects. To investigate the pattern of selective pressure on exon 3, we sequenced ortholog regions of this exon in four species of New World monkeys and one gorilla. In addition, orthologous sequences of PAX9 available in public databases were also analyzed. Although several differences were identified between humans and other species, our findings support the view that strong purifying selection is acting on PAX9. New World and Old World primate lineages may, however, have different degrees of restriction for changes in this DNA region. human evolution ͉ tooth agenesis ͉ evolutionary window

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“…Hypomorphic Pax9 mutant shows a smaller lower third molar with reduced levels of mesenchymal condensation in the tooth bud-forming area (Kist et al, 2005). Another spontaneous mutant strain Tabby mouse has smaller lower first and second molars attributed to smaller tooth buds (Pispa et al, 1999).…”

Section: Odontogenic Potential Of Rat Primary Dental Placode and Sizementioning

confidence: 99%

Study of Pax6 mutant rat revealed the association between upper incisor formation and midface formation

Kriangkrai

Chareonvit

Yahagi

et al. 2006

Developmental Dynamics

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In this study, we investigated the process of supernumerary upper incisor formation in the Pax6 mutant rat, rSey 2 /rSey 2 , which exhibits a facial cleft between the medial nasal and maxillary processes. Histological investigation and epithelial labeling studies of wild type rat embryos indicated that the upper incisor develops by fusion of two primary dental placodes (PDPs) in the medial nasal process with a contribution from the epithelium of the maxillary process. In the rSey 2 /rSey 2 embryo, both PDPs are formed but they stay apart, then subsequently these PDPs independently develop into upper incisor tooth buds. In order to examine if the failure of the two placodes to fuse is due to the cleft between the maxillary and medial nasal processes, maxillary and medial nasal process fusion was inhibited with a barrier in wild type embryos. This resulted in the maintenance of the two distinct PDPs. These results demonstrate that fusion of the facial processes reduces the number of odontogenic placodes and is required to assemble all components at one site for rat upper incisor formation. The results also provide further insight into the mechanism of supernumerary incisor formation in human cleft lip conditions. Developmental Dynamics 235:2134 -2143, 2006.

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Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia

Cited by 80 publications

References 40 publications

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

Identification and Functional Analysis of Two Novel <i>PAX9</i> Mutations

Natural selection and molecular evolution in primatePAX9gene, a major determinant of tooth development

Study of Pax6 mutant rat revealed the association between upper incisor formation and midface formation

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