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

Abstract

Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible 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: 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 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 our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKII levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.

Loss of ATP2C1 function promotes trafficking and degradation of NOTCH1: Implications for Hailey‐Hailey disease

“…Interestingly, the expression of ATP2C1 was strongly downregulated in cells derived from lesional skin areas but not in cultured keratinocytes originating from unaffected skin areas of the same patients 14 . We and others also observed that keratinocytes as well as the skin tissue derived from lesional skin of HHD‐patients have a reduced expression of NOTCH1 protein 14,15,18,20 . Conversely, reducing the expression of ATP2C1 gene by siRNA‐mediated silencing, we found increased NOTCH1 expression levels 18 .…”

“…14 We and others also observed that keratinocytes as well as the skin tissue derived from lesional skin of HHD-patients have a reduced expression of NOTCH1 protein. 14,15,18,20 Conversely, reducing the expression of ATP2C1 gene by siRNA-mediated silencing, we found increased NOTCH1 expression levels. 18 Thus, it could be that the discrepancy in NOTCH1 expression between siRNA-ATP2C1-treated and the lesion-derived keratinocytes underlies a differential effect on NOTCH1 activity by short-and long-term inactivation of ATP2C1 and could represent a pathogenetic mechanism of the disease manifestation.…”

“…In our studies, we found that p63 and NOTCH1, two important factors that regulate proliferation, differentiation, cell adhesion, and other functions in keratinocytes, are negatively regulated in keratinocytes derived from lesional skin of HHD-patients. 14 Similarly, Li et al 15 reported that the expression of levels of both NOTCH1 and p63 was lower in the lesional skin tissues of HHD patients compared to the healthy control skin. Having identified some of the relevant pathways in the HHD pathogenesis, a more careful dissection of specific components and underlying molecular mechanisms may now be addressed.…”

Identification of Six microRNAs as Potential Biomarkers for Pemphigus Vulgaris: From Diagnosis to Pathogenesis

“…For the hundreds of target genes of the six upregulated miRNAs, NOTCH1, SOCS3, and BCL2 may have significant integration with the pathogenesis of PV. NOTCH1 is the shared target mRNA of miR-181a-5p and miR-326 and is a crucial mediator for the homeostasis of keratinocytes, which was found to be suppressed by miR-125b and decreased in Hailey–Hailey disease [ 29 , 30 ]. The decreased level of NOTCH1 was related to the oxidative stress of keratinocytes, which contributed to the disease activity of pemphigus vulgaris [ 31 ].…”

A novel ATP2C1 mutation (c.1840-1G>A) in a sporadic case of isolated perianal Hailey-Hailey disease with human papillomavirus type 58 infection

“…It is caused by ATP2C1 mutation, encoding secretory pathway Ca 2+ /Mn 2+ -ATPase 1 (SPCA1). 1 , 2 Updated on May 16, 2022, 264 public variants have been documented in ATP2C1 LOVD database ( https://databases.lovd.nl/shared/genes/ATP2C1 ). We report a sporadic case of isolated perianal Hailey-Hailey disease caused by a novel splicing mutation of ATP2C1 with Human Papillomavirus (HPV) 58 infection.…”