Publications by authors named "Cristina Has"

155 Publications

[Wound therapy with cold atmospheric plasma in severe recessive dystrophic epidermolysis bullosa : A pilot study].

Hautarzt 2021 Sep 14. Epub 2021 Sep 14.

Klinik und Poliklinik für Dermatologie und Venerologie, Universitätsmedizin Rostock, Strempelstr. 13, 18057, Rostock, Deutschland.

Background: Cold atmospheric pressure plasma (CAP) has antimicrobial and wound-healing properties. Patients affected by severe autosomal recessive dystrophic epidermolysis bullosa (RDEB) suffer from widespread, difficult-to-treat wounds, which require complex wound management.

Objective: In a pilot project, we investigated over a period of 5 months the response and tolerability of a CAP wound therapy in a 21-year-old and a 28-year-old female patient with severe generalized RDEB and following cutaneous squamous cell cancer (cSSC) in the older patient.

Materials And Methods: In both patients, diagnosis of RDEB was confirmed by molecular genetics. Individual- and patient-specific wound therapy was continued during the study period, and additionally CAP therapy with a dielectric barrier discharge (DBE) device was initiated. CAP treatment was performed for 90 s per wound and could be applied every day or every other day. Clinical evaluation included photographic documentation and regular interviews of patients and parents.

Results: CAP-treated wounds largely demonstrated improved wound healing and signs of a reduced bacterial contamination. Furthermore, CAP proved to prevent wound chronification. When applied on a polyester mesh, it was well-tolerated on most body sites.

Conclusion: The introduction of CAP could improve the wound management of EB patients and should be evaluated in clinical studies. The effect of CAP on cSSC development should be particularly studied.
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http://dx.doi.org/10.1007/s00105-021-04883-5DOI Listing
September 2021

Maternal Isodisomy of Chromosome 3 Combined with a Mutation in the Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome.

Genes (Basel) 2021 Jul 29;12(8). Epub 2021 Jul 29.

Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene (, MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.
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http://dx.doi.org/10.3390/genes12081164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391107PMC
July 2021

Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes.

Am J Med Genet A 2021 Jul 27. Epub 2021 Jul 27.

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.

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http://dx.doi.org/10.1002/ajmg.a.62438DOI Listing
July 2021

Hautfragilität, Nierenfehlbildungen und interstitielle Lungenerkrankung aufgrund von compound-heterozygoten ITGA3-Mutationen.

J Dtsch Dermatol Ges 2021 Jun;19(6):899-902

Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg, Universität Freiburg, Medizinische Fakultät, Freiburg im Breisgau.

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http://dx.doi.org/10.1111/ddg.14381_gDOI Listing
June 2021

Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease.

Dis Model Mech 2021 Jun 4;14(6). Epub 2021 Jun 4.

Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.

Heterozygous missense mutations in the human COL7A1 gene - coding for collagen VII - lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and - together with a relatively mild phenotype - represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.048082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214732PMC
June 2021

Autosomal recessive congenital ichthyoses (ARCI) in a "bathing-suit" distribution: progression over time.

Int J Dermatol 2021 Aug 12;60(8):e296-e297. Epub 2021 Apr 12.

Department of Dermatology, Universitätsklinikum Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/ijd.15599DOI Listing
August 2021

Skin fragility, renal malformation and interstitial lung disease due to compound heterozygous ITGA3 mutations.

J Dtsch Dermatol Ges 2021 Jun 25;19(6):899-901. Epub 2021 Mar 25.

Department of Dermatology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany.

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http://dx.doi.org/10.1111/ddg.14381DOI Listing
June 2021

Effect of small molecule eRF3 degraders on premature termination codon readthrough.

Nucleic Acids Res 2021 04;49(7):3692-3708

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Premature termination codon (PTC) readthrough is considered a potential treatment for genetic diseases caused by nonsense mutations. High concentrations of aminoglycosides induce low levels of PTC readthrough but also elicit severe toxicity. Identifying compounds that enhance PTC readthrough by aminoglycosides or reduce their toxicity is a continuing challenge. In humans, a binary complex of eukaryotic release factors 1 (eRF1) and 3 (eRF3a or eRF3b) mediates translation termination. They also participate in the SURF (SMG1-UPF1-eRF1-eRF3) complex assembly involved in nonsense-mediated mRNA decay (NMD). We show that PTC readthrough by aminoglycoside G418 is considerably enhanced by eRF3a and eRF3b siRNAs and cereblon E3 ligase modulators CC-885 and CC-90009, which induce proteasomal degradation of eRF3a and eRF3b. eRF3 degradation also reduces eRF1 levels and upregulates UPF1 and selectively stabilizes TP53 transcripts bearing a nonsense mutation over WT, indicating NMD suppression. CC-90009 is considerably less toxic than CC-885 and it enhances PTC readthrough in combination with aminoglycosides in mucopolysaccharidosis type I-Hurler, late infantile neuronal ceroid lipofuscinosis, Duchenne muscular dystrophy and junctional epidermolysis bullosa patient-derived cells with nonsense mutations in the IDUA, TPP1, DMD and COL17A1 genes, respectively. Combination of CC-90009 with aminoglycosides such as gentamicin or ELX-02 may have potential for PTC readthrough therapy.
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http://dx.doi.org/10.1093/nar/gkab194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053119PMC
April 2021

Schwere Fragilität der Haut mit postnatal letalem Ausgang bei biallelischer KRT5-Mutation.

J Dtsch Dermatol Ges 2021 Mar;19(3):440-442

Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.

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http://dx.doi.org/10.1111/ddg.14277_gDOI Listing
March 2021

Meta-Analysis of Mutations in or Identified in a Large Cohort of 224 Patients.

Genes (Basel) 2021 01 9;12(1). Epub 2021 Jan 9.

Department of Medical Sciences/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden.

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: , , , , , , , , , and . The main focus of this report is the mutational spectrum of the genes and , which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in and 27 pathogenic mutations in have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in and 25 novel mutations in . We investigated the spectrum of mutations in and in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.
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http://dx.doi.org/10.3390/genes12010080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826849PMC
January 2021

Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts.

Cells 2020 12 17;9(12). Epub 2020 Dec 17.

Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada.

We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.
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http://dx.doi.org/10.3390/cells9122702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766948PMC
December 2020

Severe skin fragility with postnatal lethal outcome due to a biallelic KRT5 mutation.

J Dtsch Dermatol Ges 2021 03 28;19(3):440-442. Epub 2020 Sep 28.

Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.

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http://dx.doi.org/10.1111/ddg.14277DOI Listing
March 2021

Epidermolysis bullosa.

Nat Rev Dis Primers 2020 09 24;6(1):78. Epub 2020 Sep 24.

Epidermolysis Bullosa Unit, Department of Dermatology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, UK.

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The study of EB has led to seminal advances in our understanding of cutaneous biology. To date, pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion. Precise diagnosis is reliant on correlating clinical, electron microscopic and immunohistological features with mutational analyses. In the absence of curative treatment, multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma. Preclinical advances in cell-based, protein replacement and gene therapies are paving the way for clinical successes with gene correction, raising hopes amongst patients and clinicians worldwide.
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http://dx.doi.org/10.1038/s41572-020-0210-0DOI Listing
September 2020

Human Papillomavirus-induced Cutaneous and Mucosal Lesions in a Patient with Rothmund-Thomson Syndrome.

Acta Derm Venereol 2020 Aug 19;100(15):adv00252. Epub 2020 Aug 19.

Department of Dermatology, Venereology and Allergology, HELIOS St Elisabeth Hospital Oberhausen, Josefstr. 3, DE-46045 Oberhausen, Germany.

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http://dx.doi.org/10.2340/00015555-3596DOI Listing
August 2020

Emergency management in epidermolysis bullosa: consensus clinical recommendations from the European reference network for rare skin diseases.

Orphanet J Rare Dis 2020 06 6;15(1):142. Epub 2020 Jun 6.

Dermatology Department, reference Centre MAGEC, Necker- Enfants Malades Hospital, Paris-Centre University, Paris, France.

Epidermolysis bullosa (EB) comprises a group of genetic disorders with the hallmark of fragility of the skin and mucosal surfaces. The severity of different types of EB varies markedly as does the occurrence of extra-cutaneous involvement and complications. A number of emergency situations may occur in the context of EB including obstruction to oral intake from oral or esophageal blisters or scarring, acute airway obstruction, acute urinary retention, sepsis and corneal erosions. Whilst general management principles apply in each of these settings, specific considerations are essential in managing EB to avoid undue trauma or damage to delicate tissues. These recommendations have been developed from a literature review and consensus from experts of the European Network for Rare Skin Disorders (ERN-Skin) to aid decision-making and optimize clinical care by non-EB expert health professionals encountering emergency situations in babies, children and adults with EB.
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http://dx.doi.org/10.1186/s13023-020-01403-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276067PMC
June 2020

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020.

Mol Diagn Ther 2020 06;24(3):299-309

Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Epidermolysis bullosa (EB) is a group of rare genetic disorders for which significant progress has been achieved in the development of molecular therapies in the last few decades. Such therapies require knowledge of mutant genes and specific mutations, some of them being allele specific. A relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs, mainly in recessive dystrophic EB. It is expected that some new drugs may emerge in the near future and that combinations of different approaches may result in improved treatment outcomes for individuals with EB.
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http://dx.doi.org/10.1007/s40291-020-00466-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264085PMC
June 2020

Disorders Caused by Genetic Mosaicism.

Dtsch Arztebl Int 2020 02;116(8):119-125

Institute of Human Genetics. University Hospital Heidelberg, Heidelberg; Institute of Human Genetics, University of Greifswald and Interfaculty Institute for Genetics and Functional Genomics, Greifswald University, Greifswald; Department of Dermatology and Venereology, University Medical Center Freiburg, Albert-Ludwigs-Universität Freiburg, Freiburg; genetikum®, Genetische Beratung und Diagnostik, Stuttgart.

Background: Genetic mosaics arise through new mutations occurring after fertiliza- tion (i.e., postzygotic mutations). Mosaics have been described in recent years as the cause of many different disorders; many of these are neurocutaneous diseases and syndromal developmental disorders, each with a characteristic phenotype. In some of these disorders, there is a genetic predisposition to the development of tumors. This article is intended as an overview of selected mosaic diseases.

Methods: This review is based on publications retrieved by a selective search in PubMed, with particular attention to recent articles in high-ranking journals dealing with asymmetric growth disturbances, focal brain malformations, mosaic diseases due to dysregulation of the RAS/RAF signaling pathway (mosaic RASopathies), and vascular malformations.

Results: The identification of postzygotic mutations has led to the reclassification of traditional disease entities and to a better understanding of their pathogenesis. Diagnosis is aided by modern next-generation sequencing (NGS) techniques that allow the detection even of low-grade mosaics. Many mosaic mutations are not detectable in blood, but only in the affected tissue, e.g., the skin. Genetic mosaic diseases often manifest themselves in the skin and brain, and by facial dysmorphism, asymmetrical growth disturbances, and vascular malformations.

Conclusion: The possibility of a mosaic disease should be kept in mind in the diag- nostic evaluation of patients with asymmetrical growth disturbances, focal neuronal migration disturbances, vascular malformations, and linear skin abnormalities. The demonstration of a postzygotic mutation often affords relief to the parents of an affected child, since this means that there is no increased risk for recurrence of the same disorder in future children. Correct classification is important, as molecular available for certain mosaic diseases, e.g., PIK3CA-related overgrowth spectrum (PROS) disorder.
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http://dx.doi.org/10.3238/arztebl.2020.0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081367PMC
February 2020

Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?

J Cutan Pathol 2020 Feb 6;47(2):186-189. Epub 2019 Nov 6.

Regenerative Medicine, Future Industries Institute, University of South Australia, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/cup.13597DOI Listing
February 2020

Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4.

Hum Mutat 2019 12 6;40(12):2318-2333. Epub 2019 Sep 6.

Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations.
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http://dx.doi.org/10.1002/humu.23883DOI Listing
December 2019

Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients.

Orphanet J Rare Dis 2019 07 24;14(1):183. Epub 2019 Jul 24.

Department of Bioengineering, Universidad Carlos III de Madrid, Leganés, Madrid, Spain.

Background: Kindler Syndrome (KS) is a rare genodermatosis characterized by skin fragility, skin atrophy, premature aging and poikiloderma. It is caused by mutations in the FERMT1 gene, which encodes kindlin-1, a protein involved in integrin signalling and the formation of focal adhesions. Several reports have shown the presence of non-melanoma skin cancers in KS patients but a systematic study evaluating the risk of these tumors at different ages and their potential outcome has not yet been published. We have here addressed this condition in a retrospective study of 91 adult KS patients, characterizing frequency, metastatic potential and body distribution of squamous cell carcinoma (SCC) in these patients. SCC developed in 13 of the 91 patients.

Results: The youngest case arose in a 29-year-old patient; however, the cumulative risk of SCC increased to 66.7% in patients over 60 years of age. The highly aggressive nature of SCCs in KS was confirmed showing that 53.8% of the patients bearing SCCs develop metastatic disease. Our data also showed there are no specific mutations that correlate directly with the development of SCC; however, the mutational distribution along the gene appears to be different in patients bearing SCC from SCC-free patients. The body distribution of the tumor appearance was also unique and different from other bullous diseases, being concentrated in the hands and around the oral cavity, which are areas of high inflammation in this disease.

Conclusions: This study characterizes SCCs in the largest series of KS patients reported so far, showing the high frequency and aggressiveness of these tumors. It also describes their particular body distribution and their relationship with mutations in the FERMT-1 gene. These data reinforce the need for close monitoring of premalignant or malignant lesions in KS patients.
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http://dx.doi.org/10.1186/s13023-019-1158-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657209PMC
July 2019

Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 "knock-out".

Matrix Biol 2019 10 11;83:48-59. Epub 2019 Jul 11.

Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address:

Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human "knock-out" of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.
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http://dx.doi.org/10.1016/j.matbio.2019.07.002DOI Listing
October 2019

[Role of the dermatologist in recognizing syndromes].

Hautarzt 2019 Jul;70(7):472-473

Klinik für Dermatologie und Venerologie, Universitätsklinikum Freiburg, Haupstr. 7, 79104, Freiburg, Deutschland.

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http://dx.doi.org/10.1007/s00105-019-4442-4DOI Listing
July 2019

Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations.

Clin Immunol 2019 11 10;208:108228. Epub 2019 Jun 10.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

This study reports a patient with severe skin disease in the context of profound immunodeficiency explained by two concomitant genetic diseases caused by two novel homozygous loss-of-function mutations in PLEC1 and CARMIL2. The work provides additional information on the clinical and immunological manifestations of CARMIL2 deficiency and highlights the particular diagnostic and therapeutic challenge represented by the concomitant presence of two rare monogenic disorders.
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http://dx.doi.org/10.1016/j.clim.2019.06.004DOI Listing
November 2019

Isolation and Culture of Epidermolysis Bullosa Cells and Organotypic Skin Models.

Methods Mol Biol 2019 ;1993:181-190

Department of Dermatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Isolation and culture of keratinocytes from patients with different types of epidermolysis bullosa are sometimes challenging, because of the inherent adhesion defects of these cells. We routinely employ a well-established protocol for in vitro culture of these cells from small skin samples remaining after diagnostic procedures are performed. Keratinocytes and fibroblast can be used for downstream expression and functional studies or for construction of in vitro organotypic cocultures. These cells maintain main common characteristics of spreading, adhesion, migration, and survival, which depend on the underlying molecular defect.
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http://dx.doi.org/10.1007/978-1-4939-9473-1_14DOI Listing
February 2020

A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation.

J Invest Dermatol 2019 10 11;139(10):2154-2163.e5. Epub 2019 May 11.

Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Trichilemmal cysts are common hair follicle-derived intradermal cysts. The trait shows an autosomal dominant mode of transmission with incomplete penetrance. Here, we describe the pathogenetic mechanism for the development of hereditary trichilemmal cysts. By whole-exome sequencing of DNA from the blood samples of 5 affected individuals and subsequent Sanger sequencing of a family cohort including 35 affected individuals, this study identified a combination of the Phospholipase C Delta 1 germline variants c.903A>G, p.(Pro301Pro) and c.1379C>T, p.(Ser460Leu) as a high-risk factor for trichilemmal cyst development. Allele-specific PCRs and cloning experiments showed that these two variants are present on the same allele. The analysis of tissue from several cysts revealed that an additional somatic Phospholipase C Delta 1 mutation on the same allele is required for cyst formation. In two different functional in vitro assays, this study showed that the protein function of the cyst-specific 1-phosphatidylinositol 4, 5-bisphosphate phosphodiesterase delta-1 protein variant is modified. This pathologic mechanism defines a monoallelic model of the two-hit mechanism proposed for tumor development and other hereditary cyst diseases.
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http://dx.doi.org/10.1016/j.jid.2019.04.015DOI Listing
October 2019

Editorial: Skin Blistering Diseases.

Front Med (Lausanne) 2019 2;6:60. Epub 2019 Apr 2.

Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany.

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http://dx.doi.org/10.3389/fmed.2019.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454141PMC
April 2019

[Neonate female with blister formation shortly after birth : Preparation for the specialist examination: part 34].

Hautarzt 2019 Apr;70(Suppl 1):31-33

Klinik und Poliklinik für Dermatologie, Fakultät für Medizin, Universitätsklinikum Freiburg, Freiburg, Deutschland.

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http://dx.doi.org/10.1007/s00105-018-4309-0DOI Listing
April 2019
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