Rare Variants in <i>LRP4</i> Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans
Piranit Nik Kantaputra,
Peeranat Jatooratthawichot,
Ploy Adisornkanj,
Panita Kitsadayurach,
Massupa Kaewgahya,
Bjorn Olsen,
Atsushi Ohazama,
Chumpol Ngamphiw,
Sissades Tongsima,
Timothy C. Cox,
James R. Ketudat Cairns
Affiliations
Piranit Nik Kantaputra
Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
Peeranat Jatooratthawichot
Center for Biomolecular Structure, Function and Application & School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
Ploy Adisornkanj
Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
Panita Kitsadayurach
Dental Department, Pang Sila Thong Hospital, Kamphaeng Phet 62120, Thailand
Massupa Kaewgahya
Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
Bjorn Olsen
Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, USA
Atsushi Ohazama
Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
Chumpol Ngamphiw
National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, Thailand
Sissades Tongsima
National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, Thailand
Timothy C. Cox
Departments of Oral & Craniofacial Sciences, School of Dentistry, and Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
James R. Ketudat Cairns
Center for Biomolecular Structure, Function and Application & School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
Background: Low density lipoprotein receptor-related protein 4 (LRP4; MIM 604270) modulates WNT/β-catenin signaling, through its binding of WNT ligands, and to co-receptors LRP5/6, and WNT inhibitors DKK1, SOSTDC1, and SOST. LRP4 binds to SOSTDC1 and WNT proteins establishing a negative feedback loop between Wnt/β-catenin, Bmp, and Shh signaling during the bud and cap stages of tooth development. Consistent with a critical role for this complex in developing teeth, mice lacking Lrp4 or Sostdc1 have multiple dental anomalies including supernumerary incisors and molars. However, there is limited evidence supporting variants in LRP4 in human dental pathologies. Methods: We clinically, radiographically, and molecularly investigated 94 Thai patients with mesiodens. Lrp4 mutant mice were generated in order to study the effects of aberrant Lrp4 expression in mice. Results: Whole exome and Sanger sequencing identified three extremely rare variants (c.4154A>G, p.Asn1385Ser; c.3940G>A, p.Gly1314Ser; and c.448G>A, p.Asp150Asn) in LRP4 in seven patients with mesiodens. Two patients had oral exostoses and two patients had root maldevelopments. Supernumerary incisors were observed in Lrp4 mutant mice. Conclusions: Our study implicates heterozygous genetic variants in LRP4 as contributing factors in the presentation of mesiodens, root maldevelopments, and oral exostoses, possibly as a result of altered WNT/β-catenin-BMP-SHH signaling.
