Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns
The purpose of this research was to investigate and identify <i>PAX9</i> gene variants in four Chinese families with non-syndromic tooth agenesis. We identified pathogenic gene variants by whole-exome sequencing (WES) and Sanger sequencing and then studied the effects of these variants o...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8142 |
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| author | Haochen Liu Hangbo Liu Lanxin Su Jinglei Zheng Hailan Feng Yang Liu Miao Yu Dong Han |
| author_facet | Haochen Liu Hangbo Liu Lanxin Su Jinglei Zheng Hailan Feng Yang Liu Miao Yu Dong Han |
| author_sort | Haochen Liu |
| collection | DOAJ |
| description | The purpose of this research was to investigate and identify <i>PAX9</i> gene variants in four Chinese families with non-syndromic tooth agenesis. We identified pathogenic gene variants by whole-exome sequencing (WES) and Sanger sequencing and then studied the effects of these variants on function by bioinformatics analysis and in vitro experiments. Four novel <i>PAX9</i> heterozygous variants were identified: two missense variants (c.191G > T (p.G64V) and c.350T > G (p.V117G)) and two frameshift variants (c.352delC (p.S119Pfs*2) and c.648_649insC(p.Y217Lfs*100)). The bioinformatics analysis showed that these variants might be pathogenic. The tertiary structure analysis showed that these four variants could cause structural damage to PAX9 proteins. In vitro functional studies demonstrated that (1) the p.Y217Lfs*100 variant greatly affects mRNA stability, thereby affecting endogenous expression; (2) the p. S119Pfs* 2 variant impairs the subcellular localization of the nuclear expression of the wild-type PAX9 protein; and (3) the four variants (p.G64V, p.V117G, p.S119Pfs*2, and p.Y217Lfs*100) all significantly affect the downstream transcriptional activity of the <i>BMP4</i> gene. In addition, we summarized and analyzed tooth missing positions caused by <i>PAX9</i> variants and found that the maxillary second molar (84.11%) and mandibular second molar (84.11%) were the most affected tooth positions by summarizing and analyzing the <i>PAX9</i>-related non-syndromic tooth agenesis positions. Our results broaden the variant spectrum of the <i>PAX9</i> gene related to non-syndromic tooth agenesis and provide useful information for future genetic counseling. |
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| spelling | doaj.art-4abe59003b2e41f5bd32b1596679a38c2023-11-30T22:24:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315814210.3390/ijms23158142Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis PatternsHaochen Liu0Hangbo Liu1Lanxin Su2Jinglei Zheng3Hailan Feng4Yang Liu5Miao Yu6Dong Han7Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaDepartment of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, ChinaThe purpose of this research was to investigate and identify <i>PAX9</i> gene variants in four Chinese families with non-syndromic tooth agenesis. We identified pathogenic gene variants by whole-exome sequencing (WES) and Sanger sequencing and then studied the effects of these variants on function by bioinformatics analysis and in vitro experiments. Four novel <i>PAX9</i> heterozygous variants were identified: two missense variants (c.191G > T (p.G64V) and c.350T > G (p.V117G)) and two frameshift variants (c.352delC (p.S119Pfs*2) and c.648_649insC(p.Y217Lfs*100)). The bioinformatics analysis showed that these variants might be pathogenic. The tertiary structure analysis showed that these four variants could cause structural damage to PAX9 proteins. In vitro functional studies demonstrated that (1) the p.Y217Lfs*100 variant greatly affects mRNA stability, thereby affecting endogenous expression; (2) the p. S119Pfs* 2 variant impairs the subcellular localization of the nuclear expression of the wild-type PAX9 protein; and (3) the four variants (p.G64V, p.V117G, p.S119Pfs*2, and p.Y217Lfs*100) all significantly affect the downstream transcriptional activity of the <i>BMP4</i> gene. In addition, we summarized and analyzed tooth missing positions caused by <i>PAX9</i> variants and found that the maxillary second molar (84.11%) and mandibular second molar (84.11%) were the most affected tooth positions by summarizing and analyzing the <i>PAX9</i>-related non-syndromic tooth agenesis positions. Our results broaden the variant spectrum of the <i>PAX9</i> gene related to non-syndromic tooth agenesis and provide useful information for future genetic counseling.https://www.mdpi.com/1422-0067/23/15/8142tooth agenesis<i>PAX9</i> variantsfunctional studiesphenotypic analysis |
| spellingShingle | Haochen Liu Hangbo Liu Lanxin Su Jinglei Zheng Hailan Feng Yang Liu Miao Yu Dong Han Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns International Journal of Molecular Sciences tooth agenesis <i>PAX9</i> variants functional studies phenotypic analysis |
| title | Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns |
| title_full | Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns |
| title_fullStr | Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns |
| title_full_unstemmed | Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns |
| title_short | Four Novel <i>PAX9</i> Variants and the <i>PAX9</i>-Related Non-Syndromic Tooth Agenesis Patterns |
| title_sort | four novel i pax9 i variants and the i pax9 i related non syndromic tooth agenesis patterns |
| topic | tooth agenesis <i>PAX9</i> variants functional studies phenotypic analysis |
| url | https://www.mdpi.com/1422-0067/23/15/8142 |
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