Sequence analysis of candidate genes in two Roma families with severe tooth agenesis

Abstract

Selective tooth agenesis is the most common congenital disorder affecting the formation of dentition in humans. Both its forms (hypodontia and more severe oligodontia) can be found either in isolated form and they can be associated with systemic condition (syndromic tooth agenesis). In addition to previously known genes (PAX9, MSX1 and AXIN2) mutations in EDA, EDARADD and WNT10 gene were recently found to be involved in isolated forms of tooth agenesis. The objective of this study was to characterize the phenotype of affected members in two large families of Roma origin segregating severe isolated tooth agenesis with very variable phenotype and to perform mutation analysis of seven genes with aim to find causal mutation. 26 family members were clinically examined and coding regions of seven genes (MSX1, PAX9, AXIN2, EDA, EDAR, EDARADD and WNT10A) were sequenced. With exclusion of third molars, average number of missing teeth was 8.2 ± 4.9 in family 1 and 7.1 ± 2.3 in family 2. The most frequently missing teeth were maxillary lateral incisors and first premolars and mandibular central incisors. Sequencing revealed four potentially damaging variants (g.Ala40Gly in MSX1, g.Ala240Pro in PAX9, g.Pro50Ser in AXIN2 and g.Met9Ile in EDARADD); however, none of them was present in all affected family members. Variable phenotype in both families examined in this study is in favour of heterogeneous genetic cause of tooth agenesis in these families: possible interaction of 946

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective

“…The EDARADD gene is a 423-kb segment located on chromosome 1q42.3-43. Despite the fact that only four NSTA-linked missense mutations in EDARADD have been reported ( Bergendal et al, 2011 ; Arte et al, 2013 ; Gabrikova et al, 2016 ; Salvi et al, 2016 ; Martínez-Romero et al, 2019 ), the significance of EDARADD in tooth development is non-negligible. Mutant EDARADD can affect the signaling and lead to NSTA by losing its affinity for EDAR or reducing its capacity to bind to TRAF6.…”