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Molecular Biology and Treatment of Genodermatoses
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Molecular Biology and Treatment of Genodermatoses

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (1 October 2022) | Viewed by 17371

Special Issue Editor

Prof. Dr. Holm Schneider

E-Mail Website
Guest Editor
Center for Ectodermal Dysplasias & Department of Pediatrics, University Hospital Erlangen, Loschgestr. 15, 91054 Erlangen, Germany
Interests: genodermatoses; ectodermal dysplasia; gene therapy; fetal medicine

Special Issue Information

Dear Colleagues,

Genodermatoses, a heterogeneous group of congenital skin diseases, are considered to be rare disorders. Collectively, however, their frequency is much higher than expected, and some of them may lead to life-threatening complications straight after birth. Recent advances in elucidating the molecular basis of such diseases have contributed to early diagnosis, paving the way to innovative therapeutic approaches, e.g., protein replacement and gene therapies. A better molecular understanding of genodermatoses biology may also provide clues to genetic conditions that do not affect the skin primarily, but are associated with characteristic and clinically significant cutaneous symptoms.

This Special Issue will focus on translational research and clinical trials aimed at improving the lives of patients with hereditary ichthyoses, phakomatoses, increased skin fragility, photosensitivity, skin tumorigenesis, cutis laxa, or defective skin appendages. We welcome original research, review articles, opinions, clinical trial protocols or findings of clinical trials, and encourage both scientists and clinicians to share their points of view.

Prof. Dr. Holm Schneider 
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • genodermatosis
  • skin biology
  • protein replacement
  • gene therapy
  • clinical trial

Published Papers (5 papers)

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7 pages, 1048 KiB  
Article
Bothnian Palmoplantar Keratoderma: Further Delineation of the Associated Phenotype
by Laura Fertitta, Fabienne Charbit-Henrion, Stéphanie Leclerc-Mercier, Thao Nguyen-Khoa, Robert Baran, Caroline Alby, Julie Steffann, Isabelle Sermet-Gaudelus and Smail Hadj-Rabia
Genes 2022, 13(12), 2360; https://doi.org/10.3390/genes13122360 - 14 Dec 2022
Cited by 1 | Viewed by 1567
Abstract
Bothnian palmoplantar keratoderma (PPKB, MIM600231) is an autosomal dominant form of diffuse non-epidermolytic PPK characterized by spontaneous yellowish-white PPK associated with a spongy appearance after water-immersion. It is due to AQP5 heterozygous mutations. We report four patients carrying a novel AQP5 heterozygous mutation [...] Read more.
Bothnian palmoplantar keratoderma (PPKB, MIM600231) is an autosomal dominant form of diffuse non-epidermolytic PPK characterized by spontaneous yellowish-white PPK associated with a spongy appearance after water-immersion. It is due to AQP5 heterozygous mutations. We report four patients carrying a novel AQP5 heterozygous mutation (c.125T>A; p.(Ile42Asn)), and belonging to the same French family. Early palmoplantar swelling (before one year of age), pruritus and hyperhidrosis were constant. The PPK was finally characterized as transgrediens, non-progrediens, diffuse PPK with a clear delineation between normal and affected skin. The cutaneous modifications at water-immersion test, “hand-in-the-bucket sign”, were significantly evident after 3 to 6 min of immersion in the children and father, respectively. AQP5 protein is expressed in eccrine sweat glands (ESG), salivary and airway submucosal glands. In PPKB, gain of function mutations seem to widen the channel diameter of ESG and increase water movement. Thus, swelling seems to be induced by hypotonicity with water entrance into cells, while hyperhidrosis is the result of an increased cytosolic calcium concentration. Full article
(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)
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15 pages, 1017 KiB  
Article
Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update
by Nicolai Peschel, John T. Wright, Maranke I. Koster, Angus J. Clarke, Gianluca Tadini, Mary Fete, Smail Hadj-Rabia, Virginia P. Sybert, Johanna Norderyd, Sigrun Maier-Wohlfart, Timothy J. Fete, Nina Pagnan, Atila F. Visinoni and Holm Schneider
Genes 2022, 13(12), 2327; https://doi.org/10.3390/genes13122327 - 10 Dec 2022
Cited by 13 | Viewed by 5763
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)
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7 pages, 513 KiB  
Article
Oculo-Cutaneous Albinism Type 4 (OCA4): Phenotype-Genotype Correlation
by Ester Moreno-Artero, Fanny Morice-Picard, Eulalie Lasseaux, Matthieu P. Robert, Valentine Coste, Vincent Michaud, Stéphanie Leclerc-Mercier, Dominique Bremond-Gignac, Benoit Arveiler and Smail Hadj-Rabia
Genes 2022, 13(12), 2198; https://doi.org/10.3390/genes13122198 - 23 Nov 2022
Cited by 2 | Viewed by 2798
Abstract
Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations in at least 20 different genes have been identified. Oculo-cutaneous Albinism type IV (OCA4) is the most [...] Read more.
Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations in at least 20 different genes have been identified. Oculo-cutaneous Albinism type IV (OCA4) is the most frequent form in Asia but has been reported in all populations, including Europeans. Little is known about the genotype-phenotype correlation. We identified two main phenotypes via the analysis of 30 OCA4 patients with a molecularly proven diagnosis. The first, found in 20 patients, is clinically indistinguishable from the classical OCA1 phenotype. The genotype-to-phenotype correlation suggests that this phenotype is associated with homozygous or compound heterozygous nonsense or deletion variants with frameshift leading to translation interruption in the SLC45A2 gene. The second phenotype, found in 10 patients, is characterized by very mild hypopigmentation of the hair (light brown or even dark hair) and skin that is similar to the general population. In this group, visual acuity is variable, but it can be subnormal, foveal hypoplasia can be low grade or even normal, and nystagmus may be lacking. These mild to moderate phenotypes are associated with at least one missense mutation in SLC45A2. Full article
(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)
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8 pages, 1944 KiB  
Article
Congenital Nail Disorders among Children with Suspected Ectodermal Dysplasias
by Sigrun Maier-Wohlfart, Carmen Aicher, Ines Willershausen, Nicolai Peschel, Udo Meißner, Lina Gölz and Holm Schneider
Genes 2022, 13(11), 2119; https://doi.org/10.3390/genes13112119 - 15 Nov 2022
Viewed by 4089
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)
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11 pages, 531 KiB  
Study Protocol
Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia
by Holm Schneider, Smail Hadj-Rabia, Florian Faschingbauer, Christine Bodemer, Dorothy K. Grange, Mary E. Norton, Riccardo Cavalli, Gianluca Tadini, Holger Stepan, Angus Clarke, Encarna Guillén-Navarro, Sigrun Maier-Wohlfart, Athmane Bouroubi and Florence Porte
Genes 2023, 14(1), 153; https://doi.org/10.3390/genes14010153 - 6 Jan 2023
Cited by 2 | Viewed by 2489
Abstract
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or [...] Read more.
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls. Full article
(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)
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