• Ectodysplasin A1
• Human pulp stem cells
• Migration
• Odontogenic differentiation
• Proliferation
• c-FOS

• Humans
• Dental Pulp/cytology
• Cell Proliferation/genetics
• Cell Differentiation/genetics
• Odontogenesis/genetics
• Stem Cells/physiology
• Stem Cells/cytology
• Ectodysplasins/genetics
• Cell Movement
• Cells, Cultured

• H2022206246 Natural Science Foundation of Hebei Province

• De novo pathogenic variant
• EDA
• TNF domain
• XLHED
• furin cleavage

• EDA gene
• PTMs
• in silico analysis
• molecular docking
• molecular simulation

• dental diseases
• disease genetics

Ectodermal dysplasia (ED) is a diverse group of genetic disorders caused by congenital defects of two or more ectodermal-derived body structures, namely, hair, teeth, nails, and some glands, e.g., sweat glands. Molecular pathogenesis of ED involves mutations of genes encoding key proteins of major developmental pathways, including ectodysplasin (EDA) and wingless-type (WNT) pathways. The most common ED phenotype is hypohidrotic/anhidrotic ectodermal dysplasia (HED) featuring hypotrichosis, hypohidrosis/anhidrosis, and hypodontia. Molecular diagnosis is fundamental for disease management and emerging treatments. We used targeted next generation sequencing to study EDA, EDAR, EDARADD, and WNT10A genes in 45 Egyptian ED patients with or without hypohidrosis. We present genotype and phenotype data of 28 molecularly-characterized patients demonstrating genetic heterogeneity, variable expressivity, and intrafamilial phenotypic variability. Thirteen mutations were reported, including four novel EDA mutations, two novel EDARADD, and one novel EDAR mutations. Identified mutations congregated in exons encoding key functional domains. EDA is the most common gene contributing to 85% of the identified Egyptian ED genetic spectrum, followed by EDARADD (10%) and EDAR (5%). Our cohort represents the first and largest cohort from North Africa where more than 60% of ED patients were identified emphasizing the need for exome sequencing to explore unidentified cases.

• EDA
• EDAR
• EDARADD
• WNT10A
• ectodermal eysplasia
• ectodysplasin A
• hypodontia
• hypohidrotic ectodermal eysplasia
• oligodontia

Causative variants in genes of the EDA/EDAR/NF‐κB pathway, such as EDA and EDARADD, have been widely identified in patients with non‐syndromic tooth agenesis (NSTA). However, few cases of NSTA are due to ectodysplasin‐A receptor (EDAR) variants. In this study, we investigated NSTA‐associated variants in Chinese families.

Peripheral blood samples were collected from the family members of 24 individuals with NSTA for DNA extraction. The coding region of the EDA gene of the 24 probands was amplified by PCR and sequenced to investigate new variants. Whole‐exome sequencing and Sanger sequencing were then performed for probands without EDA variants detected by PCR.

A novel missense variant EDAR c.338G>A (p.(Cys113Tyr)) was identified in one family. In addition, three known EDA variants (c.865C>T, c.866G>A, and c.1013C>T) were identified in three families. Genotype–phenotype correlation analysis of EDAR gene mutation showed that NSTA patients were most likely to lose the maxillary lateral incisors and the maxillary central incisors were the least affected. The phenotype of mutations at codon 289 of EDA in NSTA affected patients was characterized by lateral incisors loss, rarely affecting the maxillary first molars.

A novel EDAR missense variant c.338G>A (p.(Cys113Tyr)) was identified in a family with NSTA, extending the mutation spectrum of the EDAR gene. Genotype–phenotype correlation analyses of EDAR and EDA mutations could help to improve disease status prediction in NSTA families.

• EDA gene
• EDAR gene
• missense variant
• non-syndromic tooth agenesis

• ectodysplasin a
• hypohidrotic ectodermal dysplasia
• missense mutation
• tooth abnormalities

• Child, Preschool
• China
• Ectodermal Dysplasia 1, Anhidrotic/ethnology
• Ectodermal Dysplasia 1, Anhidrotic/genetics
• Ectodermal Dysplasia 1, Anhidrotic/physiopathology
• Ectodysplasins/genetics
• Female
• Genetic Predisposition to Disease
• Humans
• Luciferases/genetics
• Male
• Mutation, Missense/genetics
• Pedigree
• Polymerase Chain Reaction/methods

• Biodegradable materials
• Cytokines
• Spatial-temporal control of drug release
• Tooth development
• Tooth regeneration

• Biodegradable Plastics/therapeutic use
• Cytokines/genetics
• Drug Liberation/physiology
• Humans
• Regeneration/drug effects
• Tissue Engineering
• Tooth/drug effects
• Tooth/growth & development
• Tooth Loss/drug therapy
• Tooth Loss/genetics
• Tooth Loss/pathology

• National Key R&D Program of China
• National Natural Science Foundation of China
• Natural Science Foundation of Guangdong Province
• Sun Yat-sen University
• Science and Technology Program of Guangzhou
• Young Elite Scientist Sponsorship Program by CAST

• Ectodysplasin A gene
• Sanger sequencing
• gene diagnosis
• hypohidrotic ectodermal dysplasia
• novel mutation

Despite much progress in understanding the genetics of syndromic tooth agenesis (TA), the causes of the most common, isolated TA remain elusive. Recent studies have identified novel genes and variants contributing to the etiology of TA, and revealed new pathways in which tooth development genes belong. Further, the use of new research approaches including next-generation sequencing has provided increased evidence supporting an oligogenic inheritance model for TA, and may explain the phenotypic variability of the condition. In this review, we present current knowledge about the genetic mechanisms underlying syndromic and isolated TA in humans, and highlight the value of incorporating next-generation sequencing approaches to identify causative and/or modifier genes that contribute to the etiology of TA.

• etiology
• gene
• inheritance
• tooth agenesis

• R03 DE024596 NIDCR NIH HHS

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Ectodermal dysplasias refer to a large group of inherited disorders characterized by developmental defects in tissues of ectodermal origin. The study of these conditions has been instrumental in the discovery of biological pathways involved in the regulation of epithelial tissue morphogenesis. In this report, through the delineation of the molecular basis of a novel form of autosomal recessive ectodermal dysplasia, we identified a new key player in ectodermal development. We detected a number of mutations in TSPEAR co-segregating with abnormal hair and tooth development in three families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR was found to be strongly expressed in murine hair and tooth. Using a reporter assay, we showed that it regulates Notch activity. Accordingly, NOTCH1 expression was altered in patient skin, and NOTCH1, as well as many of its known targets, was down-regulated in TSPEAR deficient keratinocytes. Moreover, Tspear silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch pathway. As such, these new data are likely to lead to further investigations aimed at characterizing the role of Notch signaling pathway in other forms of ectodermal dysplasias as well as acquired hair and tooth pathologies.

• Animals
• Cell Differentiation/genetics
• DNA Mutational Analysis
• Ectodermal Dysplasia/genetics
• Ectodermal Dysplasia/pathology
• Frameshift Mutation/genetics
• Gene Expression Regulation, Developmental
• Hair Follicle/growth & development
• Humans
• Mice
• Morphogenesis/genetics
• Pedigree
• Proteins/genetics
• Receptor, Notch1/biosynthesis
• Receptor, Notch1/genetics
• Signal Transduction/genetics
• Tooth/growth & development
• Tooth/metabolism

• Donation of Israel and Ruth Ram
• Center for Nanoscience and Nanotechnology at Tel-Aviv University