Novel PAX9 Mutations Cause Non-syndromic Tooth Agenesis

Abstract

PAX9 is a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis. In Pax9-null mice, tooth development is arrested at the bud stage. In humans, heterozygous mutations in PAX9 have been associated with non-syndromic tooth agenesis, predominantly in the molars. Here, we report 2 novel mutations in the paired domain of PAX9, a three-nucleotide deletion (73-75 delATC) and a missense mutation (C146T), in two unrelated Japanese patients with non-syndromic tooth agenesis. The individual with the 73-75del ATC mutation was missing all maxillary molars and mandibular second and third molars. The individual with the C146T mutation was missing the mandibular central incisors, maxillary second premolars, and first molars, along with all second and third molars. Both mutations affected amino acids that are highly conserved among different species and are critical for DNA binding. When both mutants were transfected to COS7 cells, nuclear localization of PAX9 proteins was not affected. However, reduced expression of the mutant proteins and almost no transcriptional activity of the target BMP4 gene were observed, suggesting haploinsufficiency of PAX9 as the cause of non-syndromic tooth agenesis.

Hypodontia: An Update on Its Etiology, Classification, and Clinical Management

“…Over 300 genes are expressed and involved in tooth morphogenesis, including MSX1, PAX9, AXIN2, EDA, SPRY2, TGFA, SPRY4, WNT10A, FGF3, FGF10, FGFR2, and BMP4 [23, 55, 56]. Among these genes, PAX9 (paired box gene 9), MSX1 (muscle segment homeobox 1), AXIN2 (axis inhibition protein 2), and EDA (ectodysplasin A) are the most frequently reported genes associated with nonsyndromic hypodontia [6, 57–60]. These all have roles in both signalling pathways and in mediating the signal transduction cascades [56].…”

“…PAX9 is a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis [60], with mutations in this gene being implicated in arresting tooth development at the bud stage. Heterozygous mutations in PAX9, in humans, have been associated with nonsyndromic tooth agenesis [2].…”

Prognostic value of PAX9 in patients with esophageal squamous cell carcinoma and its prediction value to radiation sensitivity

“…Due to the G quadruplex-forming region located near exon 1, which is present in all the known sequenced placental mammals, PAX9 intron 1 serves a key role in splicing efficiency (23,24). As a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis, heterozygous mutations in PAX9 have been associated with non-syndromic tooth agenesis, predominantly in the molars (25–28). In the last decade, the abnormal expression of the PAX9 gene, which is associated with the tumorigenesis, development, invasion and metastasis of many types of cancer, was observed in a variety of malignant human tumors (29,30).…”

Prevalence of maxillary lateral incisor agenesis and associated skeletal characteristics in an orthodontic patient population

“…[10] PAX9 also plays a role in the absence of wisdom teeth. [11][12][13] Cobourne reported that tooth agenesis appear to represent a complex multifactorial phenotype, which is influenced by several factors including gene function, epigenetic influences, environmental interaction and developing timing. [9] Several studies have been directed to determine the prevalence of congenitally missing upper lateral incisors in different populations.…”