title: Oxidative stress and mitochondrial dysfunction in Kindler syndrome.
abstract: BACKGROUND
  Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.
  
  
  METHODS
  Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.
  
  
  RESULTS
  Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.
  
  
  CONCLUSIONS
  This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. elisabet.zapatero@ciemat.es.|Regenerative Medicine Unit. Departament of Basic Research, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. elisabet.zapatero@ciemat.es.|Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. elisabet.zapatero@ciemat.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. elisabet.zapatero@ciemat.es.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zapatero-Solana
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. j.luis.garcia@uv.es.|Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain. j.luis.garcia@uv.es.|Fundación Investigación Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Valencia, Spain. j.luis.garcia@uv.es.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. sguerrer@ing.uc3m.es.|Regenerative Medicine Unit. Departament of Basic Research, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. sguerrer@ing.uc3m.es.|Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. sguerrer@ing.uc3m.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. sguerrer@ing.uc3m.es.
authors.forename: Sara
authors.initials: S
authors.lastname: Guerrero-Aspizua
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. mgdiez@ing.uc3m.es.|Regenerative Medicine Unit. Departament of Basic Research, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. mgdiez@ing.uc3m.es.|Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. mgdiez@ing.uc3m.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. mgdiez@ing.uc3m.es.
authors.forename: Marta
authors.initials: M
authors.lastname: García
authors.affiliation: Servei de Dermatologia, Hospital del Mar, Parc de Salut Mar, Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. 93828@parcdesalutmar.cat.
authors.forename: Agustí
authors.initials: A
authors.lastname: Toll
authors.affiliation: Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. dra.baselga@gmail.com.
authors.forename: Eulalia
authors.initials: E
authors.lastname: Baselga
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia, Spain. maria.duran@uv.es.
authors.forename: Maria
authors.initials: M
authors.lastname: Durán-Moreno
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. jelena.markovic@uv.es.|Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain. jelena.markovic@uv.es.|Fundación Investigación Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Valencia, Spain. jelena.markovic@uv.es.
authors.forename: Jelena
authors.initials: J
authors.lastname: Markovic
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia, Spain. j.manuel.garcia@uv.es.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. cconti@ing.uc3m.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. cconti@ing.uc3m.es.
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Conti
authors.affiliation: Department of Dermatology, Medical Centre-University of Freiburg, Freiburg, Germany. cristina.has@uniklinik-freiburg.de.
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. fernando.larcher@ciemat.es.|Regenerative Medicine Unit. Departament of Basic Research, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. fernando.larcher@ciemat.es.|Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. fernando.larcher@ciemat.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. fernando.larcher@ciemat.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Larcher
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. federico.v.pallardo@uv.es.|Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain. federico.v.pallardo@uv.es.|Fundación Investigación Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Valencia, Spain. federico.v.pallardo@uv.es.
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Valencia, Spain. marcela.delrio@uc3m.es.|Regenerative Medicine Unit. Departament of Basic Research, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain. marcela.delrio@uc3m.es.|Department of Bioengineering, Universidad Carlos III de Madrid (UC3M), Madrid, Spain. marcela.delrio@uc3m.es.|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain. marcela.delrio@uc3m.es.
authors.forename: Marcela
authors.initials: M
authors.lastname: Del Rio
mesh_terms: D000293:Adolescent; D000369:Aged, 80 and over; D001768:Blister / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004820:Epidermolysis Bullosa / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology*; D010510:Periodontal Diseases / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology; D010787:Photosensitivity Disorders / Q000175:diagnosis* / Q000378:metabolism* / Q000503:physiopathology