Glutathione S-transferase Ï´-subunit as a phenotypic suppressor of pmr1Δ strain, the Kluyveromyces lactis model for Hailey-Hailey disease.

BACKGROUND: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare, chronic and recurrent blistering disorder, histologically characterized by suprabasal acantholysis. HHD has been linked to mutations in ATP2C1, the gene encoding the human adenosine triphosphate (ATP)-powered calcium channel pump. METHODS: In this work, the genetically tractable yeast Kluyveromyces lactis has been used to study the molecular basis of Hailey-Hailey disease. The K. lactis strain depleted of PMR1, the orthologue of the human ATP2C1 gene, was used to screen a Madin-Darby canine kidney (MDCK) cDNA library to identify genetic interactors able to suppress the oxidative stress occurring in those cells. RESULTS: We have identified the Glutathione S-transferase Ï´-subunit (GST), an important detoxifying enzyme, which restores many of the defects associated with the pmr1Δmutant. GST overexpression in those cells suppressed the sensitivity to calcium chelating agents and partially re-established calcium (Ca2+) homeostasis by decreasing the high cytosolic Ca2+ levels in pmr1Δstrain. Moreover, we found that in the K. lactis mutant the mitochondrial dysfunction was suppressed by GST overexpression independently from calcineurin. In agreement with yeast results, a decreased expression of the human GST counterpart (GSTT1/M1) was observed in lesion-derived keratinocytes from HHD patients. CONCLUSIONS: These data highlighted the Glutathione S-transferase as a candidate gene associated with Hailey-Hailey disease. GENERAL SIGNIFICANCE: Kluyveromyces lactis can be considered a good model to study the molecular basis of this pathology.

Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey-Hailey disease.

BACKGROUND: Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, which is characterized clinically by erosions occurring primarily in intertriginous regions, and histologically by suprabasal acantholysis. Oxidative stress plays a specific role in the pathogenesis of HHD, by regulating the expression of factors playing an important role in keratinocyte proliferation and differentiation. AIM: Given the significance of oxidative stress in HHD, we investigated the potential effects of the antioxidant properties of an α-MSH analogue, Nle4-D-Phe7-α-MSH (afamelanotide), in HHD lesion-derived keratinocytes. RESULTS: Treatment of HHD-derived keratinocytes with afamelanotide contributed to upregulation of Nrf2 [nuclear factor (erythroid-derived 2)-like 2], a redox-sensitive transcription factor that plays a pivotal role in redox homeostasis during oxidative stress. Additionally, afamelanotide treatment restored the defective proliferative capability of lesion-derived keratinocytes. Our results show that Nrf2 is an important target of the afamelanotide signalling that reduces oxidative stress. Because afamelanotide possesses antioxidant effects, we also assessed the clinical potential of this α-MSH analogue in the treatment of patients with HHD. In a phase II open-label pilot study, afamelanotide 16 mg was administered subcutaneously as a sustained-release resorbable implant formulation to two patients with HHD, who had a number of long-standing skin lesions. For both patients, their scores on the Short Form-36 improved 30 days after the first injection of afamelanotide, and both had 100% clearance of HHD lesions 60 days after the first injection, independently of the lesion location. CONCLUSIONS: Afamelanotide is effective for the treatment of skin lesions in HHD.

Association between porphyria cutanea tarda and beta-thalassemia major.

The paper describes the first two cases of porphyria cutanea tarda associated with beta-thalassemia major. The clinical course of two female patients affected by beta-thalassemia major was complicated by the onset of porphyria cutanea tarda. Both patients were also suffering from hepatitis C virus infection, iron overload and anemia. We discuss about the role performed by some of these conditions in triggering overt porphyria cutanea tarda. An improvement of the clinical and biochemical picture of porphyria cutanea tarda in both patients was obtained with chloroquine therapy given that their chronic anemia did not permit phlebotomy.

Four novel mutations of the coproporphyrinogen III oxidase gene.

Here we report the characterization of four novel mutations and a previously described one of the coproporphyrinogen III oxidase (CPO) gene in five Italian patients affected by Hereditary Coproporphyria (HCP). Three of the novel genetic variants are missense mutations (p.Gly242Cys; p.Leu398Pro; p.Ser245Phe) and one is a frameshift mutation (p.Gly188TrpfsX45).