Rare Variants in LRP4 Are Associated with Mesiodens, Root Maldevelopment, and Oral Exostoses in Humans.

Autor:	Kantaputra PN; Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.; Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand., Jatooratthawichot P; Center for Biomolecular Structure, Function and Application & School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand., Adisornkanj P; Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.; Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.; Dental Department, Sawang Daen Din Crown Prince Hospital, Sakon Nakhon 47110, Thailand., Kitsadayurach P; Dental Department, Pang Sila Thong Hospital, Kamphaeng Phet 62120, Thailand., Kaewgahya M; Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand., Olsen B; Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, USA., Ohazama A; Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan., Ngamphiw C; National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, Thailand., Tongsima S; National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani 12120, Thailand., Cox TC; Departments of Oral & Craniofacial Sciences, School of Dentistry, and Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA., Ketudat Cairns JR; Center for Biomolecular Structure, Function and Application & School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
Jazyk:	angličtina
Zdroj:	Biology [Biology (Basel)] 2023 Jan 30; Vol. 12 (2). Date of Electronic Publication: 2023 Jan 30.
DOI:	10.3390/biology12020220
Abstrakt:	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.
Databáze:	MEDLINE
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