Homozygous variants of EDAR underlying hypohidrotic ectodermal dysplasia in three consanguineous families

Khan, Sher Alam; Rukan, Ayesha; Ullah, Asmat; Bibi, Nousheen; Humayun, Muhammad; Ullah, Wasim; Raza, Rubab; Muhammad, Noor; Ahmad, Wasim; Khan, Saadullah; E-Kalsoom, Umm

doi:10.1684/ejd.2020.3844

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…The ectodysplasin pathway, including ectodysplasin, a secreted signaling molecule of the TNF superfamily, its receptor (EDAR), and the downstream death domain adaptor (EDARADD), plays an important role in the formation of epidermal appendages in mammals [ 33 , 34 ]. The EDA/EDAR signals can be activated by β-catenin and then induce FGF20 expression, triggering the formation of the feather array and tract [ 35 , 36 ].…”

Section: Feather Follicle Development In Chickensmentioning

confidence: 99%

Molecular Regulatory Mechanisms in Chicken Feather Follicle Morphogenesis

Ji,

Zhang,

et al. 2023

Genes

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In China, the sale of freshly slaughtered chickens is becoming increasingly popular in comparison with that of live chickens, and due to this emerging trend, the skin and feather follicle traits of yellow-feathered broilers have attracted a great deal of research attention. The feather follicle originates from the interaction between the epidermis and dermis in the early embryonic stage. Feather follicle morphogenesis is regulated by the Wnt, ectodysplasin (Eda), epidermal growth factor (EGF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), sonic hedgehog (Shh), Notch, and other signaling pathways that exist in epithelial and mesenchymal cells. The Wnt pathway is essential for feather follicle and feather morphogenesis. Eda interacts with Wnt to induce FGF expression, which attracts mesenchymal cell movement and aggregates to form feather follicle primordia. BMP acts as an inhibitor of the above signaling pathways to limit the size of the feather tract and distance between neighboring feather primordia in a dose-dependent manner. The Notch/Delta pathway can interact with the FGF pathway to promote feather bud formation. While not a part of the early morphogenesis of feather follicles, Shh and BMP signaling are involved in late feather branching. This review summarizes the roles of miRNAs/lncRNA in the regulation of feather follicle and feather growth and development and suggests topics that need to be solved in a future study. This review focuses on the regulatory mechanisms involved in feather follicle morphogenesis and analyzes the impact of SNP sites on feather follicle traits in poultry. This work may help us to understand the molecular regulatory networks influencing feather follicle growth and provide basic data for poultry carcass quality.

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Section: Feather Follicle Development In Chickensmentioning

confidence: 99%

Molecular Regulatory Mechanisms in Chicken Feather Follicle Morphogenesis

Ji,

Zhang,

et al. 2023

Genes

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“…EDA signaling is mediated by EDA, EDAR, and EDARADD, which form a unique TNF ligand–receptor–adapter protein complex mainly restricted to the skin appendages of vertebrates from fish to human [ 3 ]. In humans, mutations in any of these three genes lead to ectodermal dysplasia (ED), featured by the lacking or malformation of one or more skin appendages including hair follicles, nails, teeth and eccrine sweat glands and Meibomian glands [ 4 ]. Clinically, according to whether the patient has abnormal sweat glands, ectodermal dysplasia is divided into hypohidrotic ectodermal dysplasia (HED) and hidrotic ectodermal dysplasia [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases

Yang

Mei

Jiang

et al. 2022

IJMS

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Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.

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“…Based on the clinical manifestations, TA can be divided into two sub-categories: congenital non-syndromic tooth agenesis (NSTA) and syndromic tooth agenesis (STA) ( Yu et al, 2019 ). In addition, TA is a prominent feature of more than 300 syndromes ( Dinckan et al, 2018 ), involving primarily in oro-facial cleft and ectodermal dysplasia ( Nieminen, 2009 ), including Witkop syndrome (OMIM: 189,500) ( Jumlongras et al, 2001 ), hypohidrotic ectodermal dysplasia (HED) ( Parveen et al, 2019 ; Khan et al, 2020 ), Ellis-van Creveld syndrome (EVC, OMIM: 225,500) ( Niceta et al, 2018 ), odonto-onycho-dermal dysplasia (OODD, OMIM: 257,980) ( Adaimy et al, 2007 ) and Bloch-Sulzberger syndrome (OMIM: 308,300) ( Si and Liu, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The First Report of a Missense Variant in RFX2 Causing Non-Syndromic Tooth Agenesis in a Consanguineous Pakistani Family

Khan

Muhammad

et al. 2022

Front. Genet.

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Background: The syndromic and non-syndromic congenital missing teeth phenotype is termed tooth agenesis. Since tooth agenesis is a heterogeneous disorder hence, the patients show diverse absent teeth phenotypes. Thus identifying novel genes involved in the morphogenesis of ectodermal appendages, including teeth, paves the way for establishing signaling pathways.Methods and Results: We have recruited an autosomal recessive non-syndromic tooth agenesis family with two affected members. The exome sequencing technology identified a novel missense sequence variant c.1421T > C; p.(Ile474Thr) in a regulatory factor X (RFX) family member (RFX2, OMIM: 142,765). During the data analysis eight rare variants on various chromosomal locations were identified, but the co-segregation analysis using Sanger sequencing confirmed the segregation of only two variants RFX2: c.1421T > C; p.(Ile474Thr), DOHH: c.109C > G; p.(Pro37Ala) lying in a common 7.1 MB region of homozygosity on chromosome 19p13.3. Furthermore, the online protein prediction algorithms and protein modeling analysis verified the RFX2 variant as a damaging genetic alteration and ACMG pathogenicity criteria classified it as likely pathogenic. On the other hand, the DOHH variant showed benign outcomes.Conclusion:RFX2 regulates the Hedgehog and fibroblast growth factor signaling pathways, which are involved in the epithelial and mesenchymal interactions during tooth development. Prior animal model studies have confirmed the expression of rfx2 at a developmental stage governing mouth formation. Moreover, its regulatory role and close association with ciliary and non-ciliary genes causing various dental malformations makes it a potential candidate gene for tooth agenesis phenotype. Further studies will contribute to exploring the direct role of RFX2 in human tooth development.

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Homozygous variants of EDAR underlying hypohidrotic ectodermal dysplasia in three consanguineous families

Cited by 5 publications

References 26 publications

Molecular Regulatory Mechanisms in Chicken Feather Follicle Morphogenesis

Molecular Regulatory Mechanisms in Chicken Feather Follicle Morphogenesis

Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases

The First Report of a Missense Variant in RFX2 Causing Non-Syndromic Tooth Agenesis in a Consanguineous Pakistani Family

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