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

Xiaoli Li,Zhenghui Wang,Li Li,Dingwei Zhang,Jiahui Ding

doi:10.1186/s12881-020-01056-4

Xiaoli Li, Zhenghui Wang + Show 3 more

Open Access

https://doi.org/10.1186/s12881-020-01056-4

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Abstract

BackgroundFamilial 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.MethodsGenomic 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.ResultsOne 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.ConclusionIn 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.

Highlights

Familial benign chronic pemphigus, known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis
Patients The study subjects were HHD patients enrolled in the dermatology clinic of the Second Affiliated Hospital of Xi’an Jiaotong University, and pathological biopsy was performed on the patient’s typical skin lesions to further confirm the diagnosis
By using gene sequencing and exon alignment of ATP2C1 from 4 patients, we found 4 different heterozygous mutations, including 1 synonymous mutation c.G2598A, 2 missense mutations c.C1286A and c

Summary

Introduction

Known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. Known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis, and mainly manifested as erosion, erythema, accompanied with blisters and pimples. The incidence of this disease is approximately 0.002% [1], and has no significant difference between men and women [2]. ATP2C1 mutations rarely cause skin tumors, squamous cell carcinoma and basal cell carcinoma [12, 13] in HHD lesions. It is believed that HHD development is due to insufficient gene dose

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