Although our results are consistent with a lack of association of MSX1rs12532 and the risk of unilateral NSCLP and tooth agenesis, further studies with additional SNPs and a more diverse ethnic cohort are warranted.
The variant genotype of the MSX1rs8670 SNP was the most frequent in frontal agenesis; meanwhile in the lateral agenesis NSH group, the AXIN2 rs2240308 SNP showed a higher frequency of the variant genotype, with a trend towards statistical significance.
Based on previous in vitro experiments on mutation disrupting function of Msx1 homeodomain, we assume that the heterozygous g.8177G>T nonsense mutation affects the amount and function of Msx1 protein and leads to tooth agenesis.
We conclude that this frameshift mutation in the homeodomain (which plays an essential role in DNA binding) of MSX1 gene is responsible for tooth agenesis in this family.
We also report here a novel Glu78FS MSX1 mutation in one family segregating an autosomal dominant form of severe tooth agenesis as an illustration of an evolving theme, i.e., different mutations in the same gene can result in a spectrum of dentofacial phenotypic severity.
Transcription factors PAX9 and MSX1 play crucial roles in the development of permanent teeth at the bud stage, and their loss-of-function variants have been associated with congenital tooth agenesis.
Our results for the first time demonstrates that mutations in MSX1 gene might play an important role in hypodontia cases involving pre-molars and is a risk factor for this ethnic population mainly of Arabs and is first report linking these mutations with tooth agenesis.
We identified a novel frameshift mutation of the highly conserved C-terminal domain of MSX1, known as Msx homology domain 6 (MH6), in a Japanese family with non-syndromic tooth agenesis.
We hypothesize that the variable degree of tooth agenesis observed in each affected individual may be due to sub-optimal levels of MSX1 expression during critical stages tooth development.
To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations.
The aim of the present study was to perform screening for mutations and/or polymorphisms using the capillary sequencing method in the critical regions of PAX9 and MSX1 genes in a group of 270 individuals with tooth agenesis and in 30 healthy subjects of Czech origin.
To date, the mutation spectra of non-syndromic form of familial and sporadic tooth agenesis in humans have revealed defects in various such genes that encode transcription factors, MSX1 and PAX9 or genes that code for a protein involved in canonical Wnt signaling (AXIN2), and a transmembrane receptor of fibroblast growth factors (FGFR1).
This illustrates a causative role of the T174I and L205RMSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.
Despite the high frequency of tooth agenesis, there are as yet only a restricted number of mutations in MSX1 and PAX9 that have been associated with non-syndromic tooth agenesis.
Our findings suggest that the nonsense mutation in MSX1 might have resulted in rapid degradation of the mutated transcript and caused the phenotype of tooth agenesis with cleft lip in the Chinese family.
In this study, we investigated whether the 5 known tooth-agenesis-causing MSX1 missense mutations disrupt this Pax9-potentiation effect, or if they lead to deficiencies in protein stability, protein-protein interactions, nuclear translocation, and DNA-binding.
MSX1rs1095 derived allele occurred in individuals with agenesis only, and two other mutations in this gene had been earlier associated with tooth agenesis.