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Objectives <p>For a long time, phosphate regulating endopeptidase X-linked (<i>phex</i>) gene variants have been considered the primary cause of hypophosphatemic rickets. Here, we recruited a pedigree with non-syndromic tooth agenesis (NSTA), where all patients exhibit solely the absence of mandibular central incisors, indicating a highly conserved clinical phenotype. This observation leads us to hypothesize a potential connection between <i>phex</i> variants and NSTA.</p> Materials and methods <p>Whole-exome sequencing and genetic co-segregation analysis were employed to investigate the genetic basis of NSTA in this family. To further explore this hypothesis, we used <i>phex</i> knockdown zebrafish models and dental pulp stem cells (DPSCs) from the patient (DPSCs-MUT) and normal control (DPSCs-CON) to assess tooth development and cellular functions.</p> Results <p>We identified a novel <i>PHEX</i> variant (NM_000444.5 c.1763&#xa0;A &gt; T, p.N588I) that co-segregated with the NSTA phenotype. The <i>phex</i> knockdown zebrafish displayed a tooth loss phenotype, which closely aligns with characteristics of NSTA. Additionally, DPSCs-MUT exhibited significantly reduced mineralization and proliferation capabilities compared to DPSCs-CON, along with increased enzymatic activity. These findings suggest that <i>PHEX</i> variants adversely affect DPSC function. Transcriptome sequencing analysis of the DPSCs revealed significant differences in gene expression between DPSCs-MUT and DPSCs-CON. Specifically, genes linked to the cGMP-PKG signaling pathway were abnormally expressed, implicating this pathway in the potential pathogenesis of NSTA due to <i>PHEX</i> variants.</p> Conclusions <p>Collectively, this study offers a foundation for further research on the relationship between <i>PHEX</i> variants and NSTA, which could enhance the diagnosis and treatment strategies for this condition in the future.</p> Clinical relevance <p>Our research not only advances the understanding of NSTA pathogenic mechanisms but also expands the phenotypic spectrum associated with PHEX variants, highlighting its role beyond phosphate homeostasis in the development of specific dental structures.</p>

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A novel phex gene variant causes non-syndromic tooth agenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月26日

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  • Yuhua Pan,
  • Bingqiang Hua,
  • He Wang,
  • Shenglong Tan,
  • Ting Lu,
  • Fu Xiong,
  • Dandan Ma

摘要

Objectives

For a long time, phosphate regulating endopeptidase X-linked (phex) gene variants have been considered the primary cause of hypophosphatemic rickets. Here, we recruited a pedigree with non-syndromic tooth agenesis (NSTA), where all patients exhibit solely the absence of mandibular central incisors, indicating a highly conserved clinical phenotype. This observation leads us to hypothesize a potential connection between phex variants and NSTA.

Materials and methods

Whole-exome sequencing and genetic co-segregation analysis were employed to investigate the genetic basis of NSTA in this family. To further explore this hypothesis, we used phex knockdown zebrafish models and dental pulp stem cells (DPSCs) from the patient (DPSCs-MUT) and normal control (DPSCs-CON) to assess tooth development and cellular functions.

Results

We identified a novel PHEX variant (NM_000444.5 c.1763 A > T, p.N588I) that co-segregated with the NSTA phenotype. The phex knockdown zebrafish displayed a tooth loss phenotype, which closely aligns with characteristics of NSTA. Additionally, DPSCs-MUT exhibited significantly reduced mineralization and proliferation capabilities compared to DPSCs-CON, along with increased enzymatic activity. These findings suggest that PHEX variants adversely affect DPSC function. Transcriptome sequencing analysis of the DPSCs revealed significant differences in gene expression between DPSCs-MUT and DPSCs-CON. Specifically, genes linked to the cGMP-PKG signaling pathway were abnormally expressed, implicating this pathway in the potential pathogenesis of NSTA due to PHEX variants.

Conclusions

Collectively, this study offers a foundation for further research on the relationship between PHEX variants and NSTA, which could enhance the diagnosis and treatment strategies for this condition in the future.

Clinical relevance

Our research not only advances the understanding of NSTA pathogenic mechanisms but also expands the phenotypic spectrum associated with PHEX variants, highlighting its role beyond phosphate homeostasis in the development of specific dental structures.