Identification of ATP2C1 mutations in the patients of Hailey-Hailey disease

Abstract Background: Familial benign chronic pemphigus (OMIM 169600), also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. Objective: To detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, Mir-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and Mir-203 levels were also determined. Results: In this study, one synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The calcium pump was not no longer functional due to impaired protein structures. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of Mir-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In HHD patients, these factors may be involved in the signaling pathways of HHD pathogenesis. In addition, Notch1, which was negatively regulated p63, is downregulated. Our data showed that both p63 and Mir-203 may have significant regulatory effects on Notch1 in the skin.