Deleterious Variants in WNT10A, EDAR, and EDA Causing Isolated and Syndromic Tooth Agenesis: A Structural Perspective from Molecular Dynamics Simulations.

Asia Parveen,Roquyya Gul,Muhammad Usman Mirza,Maria Iqbal,Nehal F Hassib,Syed Shoaib Ahmed,Ahsan Wahab,Mostafa I Mostafa,Hina Bashir,Amal Fiaz,Tayyaba Mobeen,Fatima Arshad,Sidra Naz,Saadullah Khan,Sher Alam Khan,Matheus Froeyen,Fareeha Ashraf,Naveed Wasif,Muhammad Shoaib,Waseem Ahmad,Noor Muhammad,Nagwa E A Gaboon ,Shuokr Qarani Aziz

doi:10.3390/ijms20215282

Abstract

The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.

Highlights

The developmental abnormalities of the ectodermal appendages, such as hypodontia/oligodontia, hypotrichosis, and hypohidrosis are a heterogeneous group of syndromic and non-syndromic disorders [1]
Hypodontia and oligodontia are the clinical manifestations of many syndromic ectodermal dysplasias (EDs)
Hypohidrotic ectodermal dysplasia (HED) is characterized by sparse-to-absent hair, partial or complete absence of dentition with the conical appearance and lack of sweating, because of malfunctioning sweat glands along with other features of skin pigmentation and prominent protruded lips [9,10,11,12]

Summary

Introduction

The developmental abnormalities of the ectodermal appendages, such as hypodontia/oligodontia, hypotrichosis, and hypohidrosis are a heterogeneous group of syndromic and non-syndromic disorders [1]. Hypodontia and oligodontia are the clinical manifestations of many syndromic ectodermal dysplasias (EDs). Pathogenic alterations in MSX1 (Msh homeobox-1, OMIM *142983), PAX9 (Paired box gene-9, OMIM *167416), AXIN2 (Axis Inhibitor-2, OMIM *604025), EDA (Ectodysplasin-A, OMIM *300451), WNT10A (Wingless-Type MMTV Integration Site Family, Member 10a, OMIM *606268), LRP6 (Low Density Lipoprotein Receptor-Related Protein-6, OMIM *616724), KREMEN1 (Kringle Domain-Containing Transmembrane Protein-1, OMIM *609898) have been reported in the literature to cause non-syndromic hypodontia/oligodontia [2,3,4,5,6,7]. Heterozygous or biallelic variations in specific genes, including EDA [Ectodysplasin-A, OMIM *300451), EDAR (Ectodysplasin-A receptor, OMIM *604095], EDARADD [Ectodysplasin-A Receptor Associated Death-Domain, OMIM *606603], IKBKG [Inhibitor of Nuclear Factor Kappa B (NF-kB) Kinase Subunit Gamma, OMIM *300248] and TRAF6 [Tumour Necrosis Factor (TNF) receptor-associated factor 6, OMIM *602355] have been reported to cause the pathogenicity of HED

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Conclusion