The influence of RUNX2 and WNT10A gene mutations on tooth number and size

Abstract

Hypodontia (tooth agenesis) is one of the most common dental anomalies in humans that occurs either in non-syndromic forms or as a part of various syndroms. Hypodontia can be a result of nucleotide substitutions in genes that are involved in tooth morphogenesis, whose products are signal molecules and transcription factors that control gene expression in different phases of tooth morphogenesis (bud, cap and bell stage). Among many genes, WNT10A (with its expression in dental epithelial tissue) and RUNX2 gene (with its expression in mesenchimal tissue) have been singled out due to their key role in odontogenesis. Mutations of genes involved in odontogenesis can lead to changes in tooth morphology, structure and the number of teeth. The aim of this study was to examine the presence of potential mutations in RUNX2 and WNT10A genes, and to determine their inheritance path in patients with isolated (non-syndromic) forms of tooth agenesis. The second part of the investigation was aimed to compare tooth dimensions in hypodontia patients and healthy controls, in order to determine whether hypodontia / olygodontia is related to potential tooth size anomalies. Mutational status for RUNX2 and WNT10A genes was determined for 24 families. The sample included 72 subjects, 29 of which had clinically confirmed tooth agenesis. Mesiodistal tooth width was measured in 25 hypodontia patients and 25 healthy controls. Genetic mutations presence was confirmed by direct sequencing. Mesiodistal tooth width was measured on digitized study models using a computer software. Mutational analysis of WNT10A gene revealed the presence of two nucleotide substitutions in the exon 2 region (rs10180544, rs141074983) and three nucleotide substitutions in exon 3 (rs121908120, rs77583146, rs146902156). Mutational analysis of RUNX2 gene revealed four nucleotide substitutions in exon 3 (rs6921145, COSM1658842, rs759395776, rs768156797) and one in exon 4 (34 insC). Mutations in WNT10A gene were present in 52% of subjects, mutations in RUNX2 gene in 59% of subjects, mutations in both genes 35% of subjects, and no mutations were found in 24% of the sample...

Hipodoncija-urodjeni nedostatak zuba, predstavlja jednu od najĉešćih razvojnih anomalija kod ljudi, i moţe biti nesindromska i sindromska. Do razvoja hipodoncije moţe doći usled izmena u genima ukljuĉenim u morfogenezu zuba, a ĉiji produkti su signalni i transkripcioni faktori, odgovorni za vremenski programiranu ekspresiju gena u fazama pupoljka, kape i zvona. Iz palete gena ukljuĉenih u odontogenezu, zbog svog kljuĉnog znaĉaja izdvaja se WNT10A gen (eksprimiran u dentalnom epitelu), i RUNX2 gen (eksprimiran u mezenhimu). Mutacije gena povezanih sa odontogenezom mogu dovesti do izmena u morfologiji, broju i strukturi zuba. Ciljevi ove studije su bili da se ispita zastupljenost potencijalnih mutacija u RUNX2 i WNT10A genima i utvrdi njihov naĉin nasledjivanja kod izolovanih (nesindromskih) formi hipodoncije. Drugi deo istraţivanja odnosio se na uporedjivanje veliĉine zuba pacijenata sa urodjenim nedostatkom zuba i zdravih pacijenata kako bi se utvrdilo da li je hipodoncija/oligodoncija povezana sa eventualnim anomalijama veliĉine zuba . Mutacioni status RUNX2 i WNT10A gena, odreĊen je kod 24 porodice (72 ispitanika), pri ĉemu je kod 29 osoba, kliniĉki potvrdjena hipodoncija. Merenje meziodistalnih širina zuba je uradjeno kod 25 pacijenata sa uroĊenim nedostatkom zuba i 25 pacijenata kontrolne grupe. Prisustvo mutacija potvrĊeno je primenom tehnike direktnog sekvenciranja, dok je odreĊivanje meziodistalnih širina zuba uraĊeno primenom 3D skenera i merenjima na digitalnim modelima u kompjuterskom programu. Mutaciona analiza WNT10A gena, pokazala je prisustvo 2 nukleotidne izmene u regionu egzona 2 (rs10180544, rs141074983) i 3 izmene u egzonu 3 (rs121908120, rs77583146, rs146902156). Mutacionom analizom RUNX2 gena utvrĊeno je prisustvo 4 nukleotidne izmene u egzonu 3 (rs6921145, COSM1658842, rs759395776, rs768156797) i jedna nukleotidna izmena u regionu egzona 4 (34 insC)...