Oxidative stress and mitochondrial dysfunction in Kindler syndrome

Orphanet Journal of Rare Diseases

Marcela Del Rio⁵  Federico V Pallardó²  Fernando Larcher⁵  Cristina Has⁶  Claudio J Conti⁵  Jose Manuel García-Verdugo³  Jelena Markovic²  Maria Durán-Moreno³  Eulalia Baselga¹  Agustí Toll⁴  Marta García⁵  Sara Guerrero-Aspizua⁵  Jose Luis García-Giménez²  Elisabeth Zapatero-Solana⁵ 

[1] Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;Fundación Investigación Hospital Clínico Universitario de Valencia, Instituto de Investigación INCLIVA, Valencia, Spain;Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia, Spain;Servei de Dermatologia, Hospital del Mar, Parc de Salut Mar, Cancer Research Program, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain;Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain;Department of Dermatology, Medical Centre-University of Freiburg, Freiburg, Germany

关键词: Genodermatosis;    Keratinocytes;    Mitochondria;    Oxidative stress;    Kindlin1;   

Others  :  1138566
DOI  :  10.1186/s13023-014-0211-8

 received in 2014-08-07, accepted in 2014-12-10,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Zapatero-Solana et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

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