Abstract
BackgroundKindler 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.MethodsPatient-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.ResultsPatient-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.ConclusionsThis is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0211-8) contains supplementary material, which is available to authorized users.
Highlights
Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer
Patient 1 (SK1) presented a homozygous mutation within the consensus sequence of the donor splice site of intron 11 (c.1371 + 4A > G) that was predicted to result in aberrant splicing of the FERMT1 pre-mRNA
Our results suggest that KS keratinocytes are cells under severe oxidative stress, a condition which could underlie some of the obscure aspects of the disease such as photoaging, photosensitivity and ultimate, the high risk of cancer development
Summary
Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. Kindler Syndrome (KS; OMIM 173650; ORPHA 2908), a rare heritable skin disorder with a complex phenotype and poorly understood pathogenesis, is characterized clinically by acral skin blisters in infancy and childhood, photosensitivity, and progressive poikiloderma [1,2,3]. KS results from recessive loss-of-function mutations in the FERMT1 (fermitin family member 1) gene that encodes the protein kindlin-1, a component of focal adhesions in epithelial cells [2,3]. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, playing an important role in keratinocyte migration, proliferation and adhesion [4,5,6,7].
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