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Hum Genomics 2023 Oct 13;171:93. doi: 10.1186/s40246-023-00539-8.
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FGFR1 variants contributed to families with tooth agenesis.

Yao S , Zhou X , Gu M , Zhang C , Bartsch O , Vona B , Fan L , Ma L , Pan Y .

BACKGROUND: Tooth agenesis is a common dental anomaly that can substantially affect both the ability to chew and the esthetic appearance of patients. This study aims to identify possible genetic factors that underlie various forms of tooth agenesis and to investigate the possible molecular mechanisms through which human dental pulp stem cells may play a role in this condition. RESULTS: Using whole-exome sequencing of a Han Chinese family with non-syndromic tooth agenesis, a rare mutation in FGFR1 (NM_001174063.2: c.103G > A, p.Gly35Arg) was identified as causative and confirmed by Sanger sequencing. Via GeneMatcher, another family with a known variant (NM_001174063.2: c.1859G > A, p.Arg620Gln) was identified and diagnosed with tooth agenesis and a rare genetic disorder with considerable intrafamilial variability. Fgfr1 is enriched in the ectoderm during early embryonic development of mice and showed sustained low expression during normal embryonic development of Xenopus laevis frogs. Functional studies of the highly conserved missense variant c.103G > A showed deleterious effects. FGFR1 (c.103G > A) was overexpressed compared to wildtype and promoted proliferation while inhibiting apoptosis in HEK293 and human dental pulp stem cells. Moreover, the c.103G > A variant was found to suppress the epithelial-mesenchymal transition. The variant could downregulate ID4 expression and deactivate the TGF-beta signaling pathway by promoting the expression of SMAD6 and SMAD7. CONCLUSION: Our research broadens the mutation spectrum associated with tooth agenesis and enhances understanding of the underlying disease mechanisms of this condition.

PubMed ID: 37833774
PMC ID: PMC10576343
Article link: Hum Genomics
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cd34 fgfr1 id4 itgb1 itk kit ptprc smad6.2 smad7 vim
GO keywords: fibroblast growth factor receptor signaling pathway [+]

Disease Ontology terms: tooth agenesis [+]

Article Images: [+] show captions
References [+] :
Bailleul-Forestier, The genetic basis of inherited anomalies of the teeth. Part 1: clinical and molecular aspects of non-syndromic dental disorders. 2008, Pubmed