A Human Stem Cell-Based System to Study the Role of TP63 Mutations in Ectodermal Dysplasias.
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ABSTRACT:
SUBMITTER: Dinella JD
PROVIDER: S-EPMC6019602 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
A Human Stem Cell-Based System to Study the Role of TP63 Mutations in Ectodermal Dysplasias.
Dinella Jason D JD Chen Jiangli J Webb Saiphone S Siegfried Elaine E Bree Alanna F AF Lakshmanachetty Senthilnath S Balaiya Velmurugan V Koster Maranke I MI Koch Peter J PJ
The Journal of investigative dermatology 20180223 7
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Project description:To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term "ectodermal dysplasia", referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options.
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Project description:The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation.The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features.
| S-EPMC1734928 | biostudies-other
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Project description:Ectodermal dysplasia (ED) is a heterogeneous group of hereditary diseases of the skin and its appendages, which are characterized by impaired development and/or homeostasis of two or more ectoderm derivatives, including: hair, teeth, nails, sweat glands and their modifications (mammary glands, for instance). The overall prevalence of ectodermal dysplasia remains precisely unknown not only in Russia, but also in the world, nor is known the contribution of individual genes to its structure. This complicates the DNA diagnosis establishment of this disease due to the lack of an accurate diagnostic algorithm and a universal cost-effective method of analysis. To date, the most highly-researched genes involved in the development of anhydrous or hypohidrotic forms of ED are EDA, EDAR, EDARADD and WNT10A. The ectodysplasin A (EDA) gene is the cause of the most common X-linked form of ED, a gene from the Wnt family (WNT10A) is responsible for the autosomal recessive form of the disease, and two other genes (EDAR and EDARADD) can cause both autosomal recessive and autosomal dominant forms. This review provides the characteristics of the genes involved in ED, their mutation spectra, the level of their expression in human tissues, as well as the interrelation of the aforementioned genes. The domain structures of the corresponding proteins are considered, as well as the molecular genetic pathways in which they are involved. Animal models for studying this disorder are also taken into consideration. Due to the cross-species genes conservation, their mutations cause the disruption of the development of ectoderm derivatives not only in humans, but also in mice, cows, dogs, and even fish. It can be exploited for a better understanding of the etiopathogenesis of ectodermal dysplasias. Moreover, this article brings up the possibility of recurrent mutations in the EDA and WNT10A genes. The review also presents data on promising approaches for intrauterine ED treatment.
| S-EPMC10643535 | biostudies-literature
Project description:We report on a cohort of 204 children referred between January 2017 and January 2022 to the German Center for Ectodermal Dysplasias, Erlangen. The most frequent reasons for referral were tooth malformations and lack of multiple teeth leading to the suspicion of an ectodermal dysplasia. Many patients also suffered from being unable to perspire. Nail abnormalities, in contrast, represented a much rarer finding, albeit the impact on some individuals was large. As ectodermal dysplasias are congenital genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands, we analyzed congenital nail disorders detected in these patients. Dystrophic or otherwise abnormal nails were evident in 17 of 18 subjects with pathogenic WNT10A or GJB6 variants but in none of 161 children with EDA variants underlying X-linked hypohidrotic ectodermal dysplasia. However, 2 of 17 children who carry mutations in EDAR or EDARADD, two other genes involved in the ectodysplasin A signaling pathway, showed nail abnormalities, such as brittle or hypoplastic nails. TP63 variants were regularly associated with nail disorders. In one girl, anonychia congenita caused by a compound heterozygous variant of the R-spondin-4 gene (RSPO4) was diagnosed. Thus, nail dysplasia is rarer among patients with ectodermal dysplasia than commonly thought.
| S-EPMC9690587 | biostudies-literature
Project description:There are many ways to classify ectodermal dysplasia syndromes. Clinicians in practice use a list of syndromes from which to choose a potential diagnosis, paging through a volume, such as Freire-Maia and Pinheiro's corpus, matching their patient's findings to listed syndromes. Medical researchers may want a list of syndromes that share one (monothetic system) or several (polythetic system) traits in order to focus research on a narrowly defined group. Special interest groups may want a list from which they can choose constituencies, and insurance companies and government agencies may want a list to determine for whom to provide (or deny) health-care coverage. Furthermore, various molecular biologists are now promoting classification systems based on gene mutation (e.g., TP63-associated syndromes) or common molecular pathways. The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by ectodermal dysplasias. It is also recognized that a new classification approach is an ongoing process and will require periodical reviews or updates. Whatever scheme is developed, however, will have far-reaching application for other groups of disorders for which classification is complicated by the number of interested parties and advances in diagnostic acumen. Consensus among interested parties is necessary for optimizing communication among the diverse groups whether it be for equitable distribution of funds, correctness of diagnosis and treatment, or focusing research efforts.
| S-EPMC2756677 | biostudies-literature
Project description:ImportanceEctodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias.ObjectiveTo establish a validated population-based cohort of patients with ectodermal dysplasia in Denmark and to assess the disease prevalence and patient characteristics.Design, setting, and participantsThis nationwide cohort study used individual-level registry data recorded across the Danish universal health care system to identify patients with ectodermal dysplasias from January 1, 1995, to August 25, 2021. A 3-level search of the Danish National Patient Registry and the Danish National Child Odontology Registry was conducted to identify patients with diagnosis codes indicative of ectodermal dysplasias; patients registered in the Danish RAREDIS Database, the Danish Database of Genodermatoses, and local databases were also added. The search results underwent diagnosis validation and review of clinical data using medical records. Of 844 patient records suggestive of ectodermal dysplasias, 791 patients (93.7%) had medical records available for review. Positive predictive values of the diagnosis coding were computed, birth prevalence was estimated, and patient characteristics were identified. Data analysis was performed from May 4 to December 22, 2023.ResultsThe identified and validated study cohort included 396 patients (median [IQR] age at diagnosis, 13 [4-30] years, 246 females [62.1%]), of whom 319 had confirmed ectodermal dysplasias and 77 were likely cases. The combined positive predictive value (PPV) for ectodermal dysplasia-specific diagnosis codes was 67.0% (95% CI, 62.7%-71.0%). From 1995 to 2011, the estimated minimum birth prevalence per 100 000 live births was 14.5 (95% CI, 12.2-16.7) for all ectodermal dysplasias and 2.8 (95% CI, 1.8-3.8) for X-linked hypohidrotic ectodermal dysplasias. A molecular genetic diagnosis was available for 241 patients (61%), including EDA (n = 100), IKBKG (n = 55), WNT10A (n = 21), TRPS1 (n = 18), EDAR (n = 10), P63 (n = 9), GJB6 (n = 9), PORCN (n = 7), and other rare genetic variants.Conclusions and relevanceThe findings of this nationwide cohort study indicate that the prevalence of ectodermal dysplasias was lower than previously reported. Furthermore, PPVs of the search algorithms emphasized the importance of diagnosis validation. The establishment of a large nationwide cohort of patients with ectodermal dysplasias, including detailed clinical and molecular data, is a unique resource for future research in ectodermal dysplasias.
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Project description:Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central alpha -helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.
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Project description:Mutations in the WNT10A gene were first detected in the rare syndrome odonto-onycho-dermal dysplasia (OODD, OMIM257980) but have now also been found to cause about 35-50% of selective tooth agenesis (STHAG4, OMIM150400), a common disorder that mostly affects the permanent dentition. In our random sample of tooth agenesis patients, 40% had at least one mutation in the WNT10A gene. The WNT10A Phe228Ile variant alone reached an allele frequency of 0.21 in the tooth agenesis cohort, about 10 times higher than the allele frequency reported in large SNP databases for Caucasian populations. Patients with bi-allelic WNT10A mutations have severe tooth agenesis while heterozygous individuals are either unaffected or have a mild phenotype. Mutations in the coding areas of the WNT10B gene, which is co-expressed with WNT10A during odontogenesis, and the WNT6 gene which is located at the same chromosomal locus as WNT10A in humans, do not contribute to the tooth agenesis phenotype.
| S-EPMC4167166 | biostudies-literature
Project description:An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).
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