title: Hailey-Hailey disease: investigation of a possible compensatory SERCA2 up-regulation and analysis of SPCA1, p63, and IRF6 expression.
abstract: Hailey-Hailey disease (HHD) is caused by heterozygous mutations in the ATP2C1 gene, encoding the secretory pathway Ca(2+) ATPase1 (SPCA1). SPCA1 and sarco/endoplasmic reticulum Ca(2+) ATPase2 (SERCA2) encoded by ATP2A2 are two essential calcium pumps needed for Ca(2+) homeostasis maintenance in keratinocytes. ATP2A2 mutations cause another hereditary skin disorder, Darier's disease (DD). Previously, the compensatory expression of SPCA1 for SERCA2 insufficiency in DD was demonstrated, but it is not known whether a similar compensatory mechanism exists in HHD. Additionally, little is known about the role of p63 and interferon regulatory factor 6 (IRF6), two important regulatory factors involved in keratinocyte proliferation and differentiation, in HHD. Here, we used the skin biopsy samples from patients with HHD and human primary keratinocytes transfected with ATP2C1 siRNA to search for potential pathogenic mechanisms in HHD. We observed normal SERCA2 levels, but reduced p63, and increased IRF6 levels in HHD epidermal tissues and SPCA1-deficient keratinocytes. This suggests that there is no compensatory mechanism by SERCA2 for the SPCA1 deficiency in HHD. Moreover, the abnormal expression of p63 and IRF6 appears to be related to SPCA1 haploinsufficiency, with down-regulation of p63 probably resulting from IRF6 overexpression in HHD. We speculate that a novel pathogenic mechanism involving SPCA1, p63, and IRF6 may play a role in the skin lesions occurring in HHD.
authors.affiliation: Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, Shaanxi, 710004, People's Republic of China.
authors.forename: Dingwei
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Tu
authors.forename: Jia
authors.initials: J
authors.lastname: Huo
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Xiao
mesh_terms: D015153:Blotting, Western / Q000379:methods; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000473:pathology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
chemical_list: C081876:CKAP4 protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases