DSpace Repository :: Browsing by Author "Palisson, Francis"

Browsing by Author "Palisson, Francis"

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A Novel Homozygous 9385 bp Deletion in the FERMT1 (KIND1) Gene in a Malaysian Family with Kindler Epidermolysis bullosa and a Review of Large Deletions
(2025) Klausegger, Alfred; Leditzky, Fabian; Krämer, Susanne; Palisson, Francis; Yubero, María; Véliz, Sebastián; Koh, Mark; Tan, Ene-Choo; Laimer, Martin; Wolfgang, Johann; Fuentes, Ignacia
Kindler Epidermolysis bullosa (KEB; OMIM 173650) is a rare autosomal recessive genodermatosis characterized by bullous poikiloderma and photosensitivity. Additional presentations include blistering, poor wound healing, skin atrophy, and increased risk of skin cancer. Most cases of KEB result from aberrations in the FERMT1 (Fermitin family member 1) gene encoding kindlin-1 and include nonsense, frameshift, splicing, and missense variants. Large deletion variants have been reported in nine cases to date. Most variants are predicted to lead to premature termination of translation and to loss of kindlin-1 function. In this study, we report on a 33-year-old male patient who presented with typical clinical manifestations of KEB. As routine molecular testing failed to obtain a diagnosis, Next Generation Sequencing (NGS) of an Epidermolysis Bullosa (EB)-specific panel was carried out followed by the determination of the deletion breakpoints and verification at the mRNA and protein levels. This approach revealed a new large homozygous deletion of ~9.4 kb in the FERMT1 gene involving exons 7 to 9. Finally, we performed a literature review on large FERMT1 deletions. The deletion is predicted to skip exons 7 to 9 within the mRNA, which results in a frameshift. The patient's phenotype is likely caused by the resulting truncated and non-functioning protein. Our report further enriches the spectrum of FERMT1 gene variants to improve genotype-phenotype correlations.
Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
(2024) Tartaglia, Grace; Fuentes, María; Pate,Neil; Varughese, Abigail; Pyung, Lauren; Pyung, Israel; Alexander, Michael; Poojan, Shiv; Cao, Qingqing; Solomon, Brenda; Padron, Zachary; Dyer, Jonathan; Mellerio, Jemima; McGrath, John; Palisson, Francis; Salas, Julio; Han, Lin; South, Andrew
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.
Case Report: Crown Resorption in a Patient With Junctional Epidermolysis Bullosa and Amelogenesis Imperfecta With LAMB3 Gene Mutations
(2021) Urzúa, Blanca; Krämer, Susanne; Morales-Bozo, Irene; Camacho, Claudia; Yubero, María Joao; Palisson, Francis; Fuentes, Ignacia; Ortega-Pinto, Ana
Background: Epidermolysis bullosa (EB) corresponds to a series of conditions characterized by extreme fragility of the skin and/or mucous membranes. Of the four main types of EB, junctional EB (JEB) is the most associated with alterations in the teeth. The purposes of this study were to determine the clinical, histopathological, and ultrastructural characteristics of teeth with amelogenesis imperfecta (AI) in a patient with JEB, and compare them with control teeth, and correlate the findings with the mutations present in the patient. Case Report: The study was conducted on a 10-year-old patient with JEB carrier of two recessive mutations in the LAMB3 gene and absence of the laminin-332 protein (LM-332), determined by immunofluorescence on a skin biopsy. The patient presents hypoplastic AI with very thin and yellow-brown colored enamel. Extraction of two permanent molars was performed due to pain and soft tissue covering the crown, resembling pulp polyp or hyperplastic gingiva. Light and scanning electron microscopy (SEM) revealed very thin enamel varying from complete absence to 60 μm, absence of normal prismatic structure, and presence of a cross-banding with a laminated appearance. The histopathological study revealed granulation tissue causing external crown resorption. Conclusion: Although coronary resorption has been reported in patients with syndromic and non-syndromic AI, this is the first clinicopathological report of coronary resorption in partially erupted teeth in patients with JEB with mutations in the LAMB3 gene and hypoplastic AI. In patients with this condition, the presence of partially erupted teeth with soft tissue covering part of the crown, without a periodontal pocket, and with a radiographic image of partial coronal radiolucency should lead to suspicion of external coronary resorption.
Cells from discarded dressings diferentiate chronic from acute wounds in patients with Epidermolysis Bullosa
(2020) Fuentes, Ignacia; Guttmann‑Gruber, Christina; Tockner, Birgit; Diem, Anja; Klausegger, Alfred; Cofré‑Araneda, Glenda; Figuera, Olga; Hidalgo, Yessia; Morandé, Pilar; Palisson, Francis; Rebolledo-Jaramillo, Boris; Yubero, María Joao; Cho, Raymond J.; Rishel, Heather I.; Marinkovich, M. Peter; Teng, Joyce M. C.; Webster, Timothy G.; Prisco, Marco; Eraso, Luis H.; Hofbauer, Josefina Piñon; South, Andrew P.
Impaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.
Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo
(2022) Cao, Qingqing; Tartaglia, Grace; Alexander, Michael; Park, Pyung Hung; Poojan, Shiv; Farshchian, Mehdi; Fuentes, Ignacia; Chen, Mei; McGrath, John A.; Palisson, Francis; Salas -Alanis, Julio; South, Andrew P.
Lack of type VII collagen (C7) disrupts cellular proteostasis yet the mechanism remains undescribed. By studying the relationship between C7 and the extracellular matrix (ECM)-associated proteins thrombospondin-1 (TSP1), type XII collagen (C12) and tissue transglutaminase (TGM2) in primary human dermal fibroblasts from multiple donors with or without the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) (n=31), we demonstrate that secretion of each of these proteins is increased in the presence of C7. In dermal fibroblasts isolated from patients with RDEB, where C7 is absent or defective, association with the COPII outer coat protein SEC31 and ultimately secretion of each of these ECM-associated proteins is reduced and intracellular levels are increased. In RDEB fibroblasts, overall collagen secretion (as determined by the levels of hydroxyproline in the media) is unchanged while traffic from the ER to Golgi of TSP1, C12 and TGM2 occurs in a type I collagen (C1) dependent manner. In normal fibroblasts association of TSP1, C12 and TGM2 with the ER exit site transmembrane protein Transport ANd Golgi Organization-1 (TANGO1) as determined by proximity ligation assays, requires C7. In the absence of wild-type C7, or when ECM-associated proteins are overexpressed, C1 proximity and intracellular levels increase resulting in elevated cellular stress responses and elevated TGFβ signaling. Collectively, these data demonstrate a role for C7 in loading COPII vesicle cargo and provides a mechanism for disrupted proteostasis, elevated cellular stress and increased TGFβ signaling in patients with RDEB. Furthermore, our data point to a threshold of cargo loading that can be exceeded with increased protein levels leading to pathological outcomes in otherwise normal cells.
Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
(2020) Has, C.; Bauer, J. W.; Bodemer, C.; Bolling, M. C.; Bruckner-Tuderman, L.; Diem, A.; Fine, J-D; Heagerty, A.; Hovnanian, A.; Marinkovich, M.P.; Martinez, A.E.; Martinez, J.A.; Moss, C.; Murrell, D.F.; Palisson, Francis; Schwieger-Briel, A.; Sprecher, E.; Tamai, K.; Uitto, J.; Woodley, D.T.; Zambruno, G.; Mellerio, J.E.
Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care
De Novo COL7A1 mutation in a patient with trisomy 21: coexistence of dystrophic epidermolysis bullosa and Down syndrome
(John Wiley & Sons, 2012) Catalán, Javiera; Rodríguez, Fernando; Yubero, María; Palisson, Francis; Gana, María; Krämer, Susanne; Repetto, Gabriela
BACKGROUND: Down syndrome (DS) is the most common autosomal chromosomal disorder. Epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin and mucous membrane fragility, with formation of blisters and erosions after minor trauma. Dystrophic EB (DEB) is inherited as an autosomal dominant (DDEB) or recessive (RDEB) trait. Both forms are caused by mutations in COL7A1, the gene coding for the type VII collagen. We report a patient affected by both conditions: DS and DDEB. METHODS: A patient with DS developed generalized blisters at the age of three months. Cytogenetic study was performed to confirm DS. Skin biopsies were examined with immunohistochemical and electron microscopy techniques to determine EB subtype. Genomic DNA was extracted from peripheral blood samples. COL7A1 mutations were screened by heteroduplex analysis using conformation-sensitive gel electrophoresis and sequencing. RESULTS: Karyotype analysis revealed trisomy 21. Histological study agreed with a DEB diagnosis. Mutational analysis showed a heterozygous c.6127G>T mutation in COL7A1, which is compatible with DDEB. Parental study suggests that c.6127G>T arises as a de novo mutation. CONCLUSIONS: This report demonstrates that EB can be associated with other common conditions and reports the case of a patient who suffered two de novo independent genetic conditions. It also contributes to expanding the knowledge and database of clinical and molecular aspects of DDEB.
Enfoque clínico del paciente con síndrome de Stevens-Johnson y necrólisis epidérmica tóxica. Parte I: Epidemiología, Diagnóstico y Factores Pronósticos
(2025) Lobos, Nelson; Valenzuela, Fernando; Molgó, Montserrat; López, Valeska; Palisson, Francis
El síndrome de Stevens-Johnson (SSJ) y la necrolisis epidérmica tóxica (NET) son manifestaciones cutáneas graves de reacciones adversas a medicamentos. Esta primera revisión es una puesta al día en los aspectos epidemiológicos, fisiopatológicos, manifestaciones clínicas, diagnósticos y pronósticos de estos cuadros. Objetivo: Establecer un enfoque clínico actualizado en torno a SSJ/NET. Métodos: Se realizó una búsqueda en bases de datos indexadas (PubMed, SciElo, LILACS), seleccionando 68 artículos y 2 guías clínicas del Ministerio de Salud de Chile (MINSAL), desde marzo hasta octubre de 2024. Resultados:SSJ/NET afecta a individuos genéticamente susceptibles con respuestas inmunitarias inapropiadas, provocadas por fármacos o factores no farmacológicos, resultando en apoptosis de queratinocitos y alta mortalidad. Se proponen tres hipótesis sobre la activación de linfocitos T: hapteno/prohapteno, interacción p-i y modelo del péptido alterado. Los mediadores clave incluyen FasL, perforinas, granzimas y granulisina. Factores genéticos, como alelos HLA y variantes del CYP450, influyen en la susceptibilidad. El diagnóstico se basa en evaluación clínica e histopatológica. La biopsia es crucial para la confirmación, aunque el inicio del tratamiento no debe retrasarse si hay alta sospecha. Los hallazgos típicos son ampollas subepidérmicas, necrosis epidérmica y queratinocitos apoptóticos. Herramientas como los algoritmos de causalidad y biomarcadores pueden ayudar a identificar SSJ/TEN tempranamente, aunque estos últimos necesitan más investigación. Conclusiones: Diagnosticar SSJ/NET es desafiante debido a su presentación clínica variable y similitudes con diagnósticos diferenciales. La biopsia es importante, pero los hallazgos histopatológicos no siempre distinguen entre formas de SSJ/NET. Las herramientas de causalidad y biomarcadores tienen potencial, pero se requiere más validación. Nuestras recomendaciones son educar al paciente con riesgo, si hay alta sospecha, el tratamiento debe iniciarse sin esperar confirmación definitiva. Por otra parte, esta revisión inicial permite fundamentar las recomendaciones establecidas en la segunda parte de la revisión.
Enfoque clínico del paciente con síndrome de Stevens-Johnson y necrólisis epidérmica tóxica: Parte II
(2025) Lobos, Nelson; Valenzuela, Fernando; López, Valeska; Alfaro-Fierro, Valeria; Palisson, Francis
El SSJ, SSJ/NET y NET son reacciones adversas graves e infrecuentes a medicamentos, que representan distintas manifestaciones de una misma enfermedad caracterizada por el denudamiento de piel y mucosas. En la literatura se han reportado resultados con corticoides sistémicos, inmunoglobulina endovenosa, ciclosporina, inhibidores de TNF-alfa, plasmaféresis e inhibidores de la Janus quinasa. Objetivo: Ser una puesta al día en el manejo integral del SJS/NET. Para aumentar la sobrevida, disminuir la aparición de secuelas y mejorar la calidad de vida. Métodos: Se realizó una búsqueda sistemática entre septiembre de 2024 y abril de 2025 en bases de datos indexadas y literatura gris, seleccionando 55 artículos y 3 guías clínicas relacionadas. Resultados: El diagnóstico de SSJ/NET debe plantearse frente a fiebre, linfopenia, lesiones cutáneas atípicas y signo de Nikolsky, siendo prioritario suspender de inmediato los medicamentos sospechosos y realizar biopsia cutánea. Se recomienda aplicar escalas que estimen mortalidad, tales como SCORTEN, ABCD-10 y CRISTEN. Hospitalizar en UCI o unidad de quemados bajo estrictas medidas de soporte vital y aislamiento. El manejo debe ser multidisciplinario e implica medidas de soporte, como reposición de fluidos, control térmico, nutrición, analgesia, tromboprofilaxis y prevención de infecciones. El tratamiento sistémico se recomienda siempre, según respuesta y evolución puede incluir corticoides, inmunoglobulina, ciclosporina, inhibidores de TNF-alfa, plasmaféresis, o en casos excepcionales JAKi. Se sugiere seguimiento durante el primer año para controlar posibles secuelas cutáneas, mucosas, visuales y psicológicas. Conclusiones: Este estudio aporta recomendaciones prácticas y actualizadas para un diagnóstico precoz, priorizar medidas de soporte vital y la elección de alternativas terapéuticas, con el fin de mejorar la sobrevida y la calidad de vida de los pacientes. El tratamiento sistémico precoz es fundamental para mejorar el pronóstico de los pacientes.
Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy
(2019) Schwieger-Briel, A.; Fuentes, Ignacia; Castiglia, D.; Barbato, A.; Greutmann, M.; Leppert, J.; Duchatelet, S.; Hovnanian, A.; Burattini, S.; Yubero, María; Ibañez-Arenas, Rodrigo; Rebolledo-Jaramillo, Boris; Gräni, C.; Ott, H.; Theiler, M.; Weibel, L.; Paller, A.S.; Zambruno, G.; Fischer, J.; Palisson, Francis; Has, C.
Inherited epidermolysis bullosa (EB) comprises rare heterogeneous disorders characterized by cutaneous and mucosal fragility. Most of the 20 proteins affected have structural functions. Recently, a previously undescribed type of EB simplex (EBS), caused by gain-of-function mutations in KLHL24, encoding KLHL24 has been identified (He et al., 2016; Lin et al., 2016). This protein seems to be involved in protein ubiquitination. Patients carrying monoallelic mutations in the translation initiation codon of KLHL24 have a characteristic clinical phenotype, showing skin defects and blistering at birth and unusual stellate scarring, skin fragility, and whorled or macular hyperpigmentation or hypopigmentation in childhood (Figure 1a–e).
Epidermolysis bullosa simplex-generalized severe due to p.Glu477Lys mutation in keratin 5: a genotype-phenotype correlation with in silico modeling analysis
(2019) Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita N.; Hovnanian, Alain; Lucky, Anne W.
Background/Objectives: Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods: In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results: Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions: Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.
Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils for NET Formation
(2019) Hoste, Esther; Maueröder, Christian; Hove, Lisette van; Catrysse, Leen; Vikkula, Hanna-Kaiza; Sze, Mozes; Maes, Bastiaan; Karjosukarso, Dyah; Martens, Liesbet; Goncalves, Amanda; Parthoens, Eef; Roelandt, Ria; Declercq, Wim; Fuentes, Ignacia; Palisson, Francis; Gonzalez, Sergio; Salas-Alanis, Julio C.; Boon, Louis; Huebener, Peter; Mulder, Klaas Willem; Ravichandran, Kodi; Saeys, Yvan; Schwabe, Robert Felix; Loo, Geert van
Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a dangerassociated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation.
Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
(2019) Atanasova, Velina S.; Pourreyron, Celine; Farshchian, Mehdi; Christian A., Brown IV; Watt, Stephen A.; Wright, Sheila; Warkala, Michael; Guttmann-Gruber, Christina; Piñón Hofbauer, Josefina; Fuentes, Ignacia; Prisco, Marco; Rashidghamat, Elham; Has, Cristina; Palisson, Francis; Hovnanian, Alain; McGrath, John A.; Mellerio, Jemima E.; Bauer, Johann; South, Andrew P.
Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.
KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients
(2025) Ramovs, Veronika; Chen, Sophia; Patra, Athina; Tjokrodirijo, Rayman; Van Veelen, Peter; Mulder, Aat; Koning, Roman; Stöger, Lauran; Hubner, Catalina; Ibañez, Rodrigo; Morales, Bernardo; Morandé, Pilar; Dell'Oro, Rosario; Poblete, Cristian; Schuster, Andrés; Joao, María; Palisson, Francis; Has, Cristina; Jongbloed, Monique; Fuentes, Ignacia; Mummery, Christine; Raymond, Karine
Aims: A striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored. Methods and results: We report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs. Conclusion: The deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.
Life-threatening complications following orthognathic surgery in a patient with undiagnosed hereditary angioedema
(Elsevier, 2013) Cifuentes, Julio; Palisson, Francis; Valladares, Salvador; Jerez, Daniel
As described in the literature, hereditary angioedema (HAE) is an autosomal dominant disease that presents with recurrent events of angioedema caused by a) deficiency or b) functional alteration of the plasma protein C1 inhibitor (C1-inh); this enzyme is involved in the regulation of the complement, kallikrein-kinin, fibrinolytic, and coagulation systems. HAE is characterized by episodes of edema in the larynx, facial structures and tissues, gastrointestinal tract, or extremities. Laryngeal edema has been reported to occur predominantly after oral surgery. We describe the case of an 18-year-old Asiatic male, reporting an unremarkable medical history, who experienced complications following orthognathic surgery. Thirty hours post-op, the patient developed severe facial, pharyngeal, and glottic edema that compromised the airway, and an emergency tracheal intubation was performed. He was tested for C1-inh plasma levels, showing a sub-normal concentration and indicating a diagnosis of HAE. The patient received fresh-frozen plasma and improved throughout the day as his condition stabilized. Several cases of HAE following oral surgery have been reported, but, to the authors' knowledge, this is the first case reported following orthognathic surgery. This patient's treatment will be described, and a literature review of the disease and management methods will be provided.
Longitudinal study of wound healing status and bacterial colonisation of Staphylococcus aureus and Corynebacterium diphtheriae in epidermolysis bullosa patients
(2022) Fuentes, Ignacia; Joao, María; Morandé, Pilar; Varela, Carmen; Orostica, Karen; Acevedo, Francisco; Rebolledo, Boris; Arancibia, Esteban; Porte, Lorena; Palisson, Francis
Epidermolysis bullosa (EB) is an inherited disorder characterised by skin fragility and the appearance of blisters and wounds. Patient wounds are often colonised or infected with bacteria, leading to impaired healing, pain and high risk of death by sepsis. Little is known about the impact of bacterial composition and susceptibility in wound resolution, and there is a need for longitudinal studies to understand healing outcomes with different types of bacterial colonisation. A prospective longitudinal study of 70 wounds from 15 severe EB patients (Junctional and Recessive Dystrophic EB) from Chile. Wounds were selected independently of their infected status. Wound cultures, including bacterial species identification, composition and Staphylococcus aureus (SA) antibiotic susceptibility were registered. Wounds were separated into categories according to their healing capacity, recognising chronic, and healing wounds. Hundred-one of the 102 wound cultures were positive for bacterial growth. From these, 100 were SA-positive; 31 were resistant to Ciprofloxacin (31%) and only seven were methicillin-resistant SA (7%). Ciprofloxacin-resistant SA was found significantly predominant in chronic wounds (**P < .01). Interestingly, atoxigenic Corynebacterium diphtheriae (CD) was identified and found to be the second most abundant recovered bacteria (31/101), present almost always in combination with SA (30/31). CD was only found in Recessive Dystrophic EB patients and not related to wound chronicity. Other less frequent bacterial species found included Pseudomonas aeruginosa, Streptococus spp. and Proteus spp. Infection was negatively associated with the healing status of wounds.
Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions
(2023) De Gregorio, Cristian; Catalán, Evelyng; Garrido, Gabriel; Morandé, Pilar; Castillo, Jimena; Muñoz, Catalina; Cofré, Glenda; Huang, Ya-Lin; Cuadra, Bárbara; Murgas, Paola; Calvo, Margarita; Altermatt, Fernando; Joao, María; Palisson, Francis; South, Andrew; Ezquer, Marcelo; Ezquer, Marcelo; Fuentes, Ignacia
Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the COL7A1 gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients. Results: In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-β1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1β and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies. Conclusions: Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients’ chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.
Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic-Consensus: Recommendations by an international panel of experts
(2020) Murrell, Dedee F; Lucky, Anne W; Salas-Alanis, Julio C; Woodley, David T; Palisson, Francis; Natsuga, Ken; Nikolic, Milos; Ramirez-Quizon, Mae; Paller, Amy S; Lara-Corrales, Irene; Barzegar, Mohammadreza Amir; Sprecher, Eli; Has, Cristina; Laimer, Martin; Bruckner, Anna L; Bilgic, Asli; Nanda, Arti; Purvis, Diana; Hovnanian, Alain; Murat-Sušić, Slobodna; Bauer, Johannes; Kern, Johannes S; Bodemer, Christine; Martin, Linda K; Mellerio, Jemima; Kowaleski, Cezary; Robertson, Susan J; Bruckner-Tuderman, Leena; Pope, Elena; Marinkovich, M Peter; Tang, Jean Y; Su, John; Uitto, Jouni; Eichenfield, Lawrence F; Teng, Joyce; Aan Koh, Mark Jean; Lee, Sang Eun; Khuu, Phuong; Rishel, Heather I; Sommerlund, Mette; Wiss, Karen; Hsu, Chao-Kai; Chiu, Tor Wo; Martinez, Anna E
Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis
(2010) Lin, Ming-Wei; Lee, Ding-Dar; Liu, Tze-Tze; Lin, Yong-Feng; Chen, Shang-Yi; Huang, Chih-Cheng; Weng, Hui-Ying; Liu, Yu-Fen; Tanaka, Akio; Arita, Ken; Lai-Cheong, Joey; Palisson, Francis; Chang, Yun-Ting; Wong, Chu-Kwan; Matsuura, Isao; McGrath, John A; Tsai, Shih-Feng
Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1–q11.2 and two pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRb), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRb through interleukin-31 signaling. In one family, we identified a point mutation in the IL31RA gene, c.1562C4T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5. The identification of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology
Novel variants impairing Sp1 transcription factor binding in the COL7A1 promoter cause mild cases of recessive dystrophic epidermolysis bullosa
(2025) Pironon, Nathalie; Gasparyan, Artyom; Yubero, María; Duchatelet, Sabine; Hovhannesyan, Kristina; Leclerc-Mercier, Stephanie; Kostandyan, Natella; Palisson, Francis; Sarkisian, Tamara; Titeux, Matthias; Fuentes, Ignacia; Hovnanian, Alain
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genodermatosis characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. RDEB is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils which form attachment structures stabilizing the cutaneous basement membrane zone. Most of the previously reported COL7A1 mutations are located in the coding or intronic regions. We describe 6 patients with localized or intermediate RDEB for whom one recessive pathogenic variant in the coding region and a second variant in the COL7A1 promoter were identified. These substitutions, three of which are novel, are localized in two Sp1 binding sites of the promoter region. DNA pull-down assay showed a drastic reduction of Sp1 binding consistent with a dramatic decrease in COL7A1 transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the COL7A1 promoter on the background of a null allele can underlie localized or intermediate RDEB. They further emphasize the functional importance of Sp1 motifs in the proximal COL7A1 promoter which should be carefully investigated for regulatory mutations in the case of RDEB with only one pathogenic variant identified in the coding or intronic regions.

Browsing by Author "Palisson, Francis"

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