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Genetic Variant of Genetic Skin Diseases
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Genetic Variant of Genetic Skin Diseases

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

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 22509

Special Issue Editor

Prof. Dr. Cristina Has

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Guest Editor
Department of Dermatology, University of Freiburg, 79104 Freiburg, Germany
Interests: mutation; genodermatosis; disorders of cornification; epidermolysis bullosa; mosaic skin disorders

Special Issue Information

The number of genetic skin disorders with known genetic defects has increased during the last decade with about 165 new disease-gene associations of which over 30 are newly recognized entities. While sequencing technologies facilitate this development, understanding how genetic variants translate into biochemical, cellular, and clinical phenotypes remains complex and involves the development of cellular or animal models and adapted tools. Nevertheless, this is a highly exciting field to explore, which opens the way to personalized medicine.

This Special Issue will contain contributions on the spectrum of genetic variants in genetic skin disorders, their consequences, and their implications for therapies. Every group of genodermatosis should be represented, those with well-known genetic background, and those in which new genes are still emerging. Besides new genes and variants that account for distinct phenotypes, concomitant occurrence of two or even three genetic disorders may cause unexpected combinations of clinical features.

Prof. Dr. Cristina Has
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

  • Mutation
  • Genodermatosis
  • Disorder of cornification
  • Mosaic skin disorders
  • Epidermolysis bullosa
  • Autoinflammatory skin disorders
  • DNA repair disorder

Published Papers (6 papers)

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Research

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14 pages, 2907 KiB  
Article
A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops
by Daniele Castiglia, Paola Fortugno, Angelo Giuseppe Condorelli, Sabina Barresi, Naomi De Luca, Simone Pizzi, Iria Neri, Claudio Graziano, Diletta Trojan, Diego Ponzin, Sabrina Rossi, Giovanna Zambruno and Marco Tartaglia
Genes 2021, 12(5), 716; https://doi.org/10.3390/genes12050716 - 11 May 2021
Cited by 4 | Viewed by 4185
Abstract
Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities [...] Read more.
Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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Review

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9 pages, 660 KiB  
Review
Xeroderma Pigmentosum: Gene Variants and Splice Variants
by Marie Christine Martens, Steffen Emmert and Lars Boeckmann
Genes 2021, 12(8), 1173; https://doi.org/10.3390/genes12081173 - 29 Jul 2021
Cited by 8 | Viewed by 3427
Abstract
The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). [...] Read more.
The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). XP is a rare autosomal recessive genetic disorder associated with UV-sensitivity and early onset of skin cancer. Recently, extensive research has been conducted on the functional relevance of splice variants and their relation to cancer. Here, we focus on the functional relevance of alternative splice variants of XP genes. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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Other

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8 pages, 1952 KiB  
Case Report
Prominent Follicular Keratosis in Multiple Intestinal Atresia with Combined Immune Deficiency Caused by a TTC7A Homozygous Mutation
by Andrea Diociaiuti, Roberta Caruso, Silvia Ricci, Rita De Vito, Luisa Strocchio, Daniele Castiglia, Giovanna Zambruno and May El Hachem
Genes 2022, 13(5), 821; https://doi.org/10.3390/genes13050821 - 04 May 2022
Cited by 2 | Viewed by 1787
Abstract
Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of [...] Read more.
Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of patients. Dermatological manifestations have been reported in a few cases. We describe a child affected with MIA-CID due to a previously unreported TTC7A homozygous missense mutation. Surgery for bowel occlusion was performed in the first days of life. The patient was totally dependent on parenteral nutrition since birth and presented severe diarrhea and recurrent infections. He underwent hematopoietic stem cell transplantation at 17 months with complete donor engraftment and partial immunity improvement. In the second year of life, he progressively developed diffuse papular follicular keratoses on ichthyosiform skin, nail clubbing, and subungual hyperkeratosis. Histopathology showed hyperkeratosis with follicular plugging and scattered apoptotic keratinocytes, visualized at an ultrastructural examination. Our findings expand the spectrum of dermatological manifestations which can develop in MIA-CID patients. Examination of further patients will allow defining whether keratinocyte apoptosis is also a disease feature. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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7 pages, 1868 KiB  
Case Report
A Familial Form of Epidermolysis Bullosa Simplex Associated with a Pathogenic Variant in KRT5
by Francesco Paduano, Emma Colao, Teresa Grillone, Marco Flavio Michele Vismara, Rosario Amato, Steven Nisticò, Chiara Mignogna, Stefano Dastoli, Fernanda Fabiani, Rossella Zucco, Francesco Trapasso, Nicola Perrotti and Rodolfo Iuliano
Genes 2021, 12(10), 1503; https://doi.org/10.3390/genes12101503 - 25 Sep 2021
Cited by 1 | Viewed by 1943
Abstract
Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in [...] Read more.
Epidermolysis bullosa simplex is a disease that belongs to a group of genodermatoses characterised by the formation of superficial bullous lesions caused by minor mechanical trauma to the skin. The skin fragility observed in the EBS is mainly caused by pathogenic variants in the KRT5 and KRT14 genes that compromise the mechanical stability of epithelial cells. By performing DNA sequencing in a female patient with EBS, we found the pathogenic variant c.967G>A (p.Val323Met) in the KRT5 gene. This variant co-segregated with EBS in the family pedigree and was transmitted in an autosomal dominant inheritance manner. This is the first report showing a familial form of EBS due to this pathogenic variant. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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10 pages, 3003 KiB  
Case Report
Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review
by Roberta Rotunno, Andrea Diociaiuti, Maria Lisa Dentici, Martina Rinelli, Michele Callea, Chiara Retrosi, Giovanna Zambruno, Emanuele Bellacchio and May El Hachem
Genes 2021, 12(5), 748; https://doi.org/10.3390/genes12050748 - 17 May 2021
Cited by 4 | Viewed by 4655
Abstract
Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the [...] Read more.
Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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9 pages, 3090 KiB  
Case Report
Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis:  Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization
by Andrea Diociaiuti, Diego Martinelli, Francesco Nicita, Claudia Cesario, Elisa Pisaneschi, Marina Macchiaiolo, Sabrina Rossi, Angelo Giuseppe Condorelli, Giovanna Zambruno and May El Hachem
Genes 2021, 12(3), 343; https://doi.org/10.3390/genes12030343 - 26 Feb 2021
Cited by 6 | Viewed by 5079
Abstract
Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) is a fatty acid elongase responsible for very long-chain fatty acid biosynthesis in the brain, retina, and skin. Heterozygous mutations in ELOVL4 gene cause Stargardt-like macular dystrophy and spinocerebellar ataxia type-34, while different homozygous mutations [...] Read more.
Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) is a fatty acid elongase responsible for very long-chain fatty acid biosynthesis in the brain, retina, and skin. Heterozygous mutations in ELOVL4 gene cause Stargardt-like macular dystrophy and spinocerebellar ataxia type-34, while different homozygous mutations have been associated with ichthyosis, spastic quadriplegia, and mental retardation syndrome in three kindred. We report the first two Italian children affected with neuro-ichthyosis due to the previously undescribed ELOVL4 homozygous frameshift variant c.435dupT (p.Ile146TyrfsTer29), and compound heterozygous variants c.208C>T (p.Arg70Ter) and c.487T>C (p.Cys163Arg), respectively. Both patients were born with collodion membrane followed by development of diffuse mild hyperkeratosis and scaling, localized erythema, and palmoplantar keratoderma. One infant displayed mild facial dysmorphism. They suffered from failure to thrive, and severe gastro-esophageal reflux with pulmonary aspiration. The patients presented axial hypotonia, hypertonia of limbs, and absent head control with poor eye contact from infancy. Visual evoked potentials showed markedly increased latency and poor morphological definition, indicative of alteration of the retro-retinal visual pathways in both patients. Ultrastructural skin examination revealed abnormalities of lamellar bodies with altered release in the epidermal granular and horny layer intracellular spaces. Our findings contribute to expanding the phenotypic and genotypic features of ELOVL4-related neuro-ichthyosis. Full article
(This article belongs to the Special Issue Genetic Variant of Genetic Skin Diseases)
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