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Updated: Aug 9, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Rare Variants in LRP4 Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans

Piranit Nik Kantaputra1,2, Peeranat Jatooratthawichot3, Ploy Adisornkanj1,2,4

  • 1Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.

Biology
|February 25, 2023
PubMed
Abstract

Insights

Genetic variants in Low density lipoprotein receptor-related protein 4 (LRP4) are linked to mesiodens and other dental anomalies. This study identified rare LRP4 variants in patients with mesiodens, suggesting a role in tooth development.

Area of Science:

  • Genetics
  • Developmental Biology
  • Oral Pathology

Background:

  • Low density lipoprotein receptor-related protein 4 (LRP4) regulates WNT/β-catenin signaling by binding WNT ligands and co-receptors.
  • LRP4 interacts with WNT inhibitors like SOSTDC1, forming a feedback loop influencing Wnt/β-catenin, Bmp, and Shh signaling during tooth development.
  • While Lrp4 deficiency causes dental anomalies in mice, evidence linking LRP4 variants to human dental pathologies is limited.

Purpose of the Study:

  • To investigate the role of Low density lipoprotein receptor-related protein 4 (LRP4) in human dental anomalies, specifically mesiodens.
  • To identify genetic variants in LRP4 associated with mesiodens and related oral pathologies.

Main Methods:

  • Clinical, radiographic, and molecular investigation of 94 Thai patients with mesiodens.
  • Generation of Lrp4 mutant mice to study the effects of aberrant Lrp4 expression.
  • Whole exome and Sanger sequencing to identify LRP4 variants in patients.

Main Results:

  • Three rare heterozygous variants in LRP4 were identified in seven patients with mesiodens.
  • Two patients presented with oral exostoses, and two with root maldevelopments.
  • Lrp4 mutant mice exhibited supernumerary incisors, consistent with findings in patients.

Conclusions:

  • Heterozygous genetic variants in LRP4 are implicated as contributing factors in mesiodens, root maldevelopments, and oral exostoses.
  • These findings suggest that altered LRP4 function may disrupt WNT/β-catenin-BMP-SHH signaling pathways crucial for tooth development.
  • The study highlights the potential role of LRP4 in human dental pathologies.
Keywords:
buccal exostosesroot anomaliesroot malformationstorus mandibularistorus palatinus

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