The role of the ATP2C1 gene in Hailey-Hailey disease

Abstract

Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis, characterized by a chronic course of repeated and exacerbated skin lesions in friction regions. The pathogenic gene of HHD was reported to be the ATPase calcium-transporting type 2C member 1 gene (ATP2C1) located on chromosome 3q21-q24. Its function is to maintain normal intracellular concentrations of Ca²⁺/Mn²⁺ by transporting Ca²⁺/Mn²⁺ into the Golgi apparatus. ATP2C1 gene mutations are reportedly responsible for abnormal cytosolic Ca²⁺/Mn²⁺ levels and the clinical manifestations of HHD. Environmental factors and genetic modifiers may also affect the clinical variability of HHD. This article aims to critically discuss the clinical and pathological features of HHD, differential diagnoses, and genetic and functional studies of the ATP2C1 gene in HHD. Further understanding the role of the ATP2C1 gene in the pathogenesis of HHD by genetic, molecular, and animal studies may contribute to a better clinical diagnosis and provide new strategies for the treatment and prevention of HHD.

Keywords: Animal model; Clinical manifestation; Gene function; Genetics; Mutation analysis; Pathogenesis.

Fig. 1

Schematic representation of Hailey–Hailey disease. a The distribution of typical HHD usually occurs in a comparatively symmetrical pattern, exhibiting a generalized and bilateral involvement. b The type 1 segmental HHD reflects a localized postzygotic mutation that occurs at an early stage of embryogenesis, resulting in heterozygosity and a segmental cutaneous disease. c The type 2 segmental HHD reflects a germline mutation in combination with somatic loss of heterozygosity in embryos, which develops a nonsegmental, diffuse distribution of skin lesions with a homozygous or hemizygous state of the underlying mutation in more severely affected segmental areas. d Histopathology section of HHD, showing acantholysis resulted from disruption of cell–cell contacts, which appears like a dilapidated brick wall (H&E stain; ×100; Olympus BX53, Japan)

Fig. 2

Schematic representation of the reported ATP2C1 gene mutations in Hailey–Hailey disease. SPCA1 consists of ten transmembrane domains, a phosphorylation domain, a calcium binding site, and a magnesium binding site. All ATP2C1 mutations are described according to the ATP2C1 isoform 1a (NM_014382.3, NP_055197.2). The exon 27 of the ATP2C1 gene is not drawn to scale (as indicated by dashed lines)