A novel splice‐site mutation in the ATP2C1 gene of a Chinese family with Hailey‐Hailey disease

Abstract

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is an autosomal dominant genodermatosis. It is characterized by erosions, blisters and erythematous plaques at sites of friction or intertriginous areas. The pathogenic gene of HHD has been revealed as the ATPase secretory pathway Ca 2+ transporting 1 gene (ATP2C1), which encodes the protein, secretory pathway Ca 2+ /Mn 2+ -ATPase 1 (SPCA1). ATP2C1 gene mutations are responsible for HHD by resulting in abnormal Ca 2+ homeostasis in the skin and giving rise to acantholysis, a characteristic pathology of HHD. In this study, a four-generation family containing three HHD sufferers was recruited. Direct sequencing of the ATP2C1 gene was performed in the proband and other available family members. Reverse-transcriptase polymerase chain reaction analysis was conducted to show the potential variant effect on ATP2C1 splicing.A novel heterozygous c.325-2A>G transition at the splice acceptor site of intron 4 in the ATP2C1 gene was identified, and it co-segregated with the disease in this family. The mutation resulted in exon 5 skipping and an in-frame deletion of 12 amino acids (p.Ala109_Gln120del) in SPCA1. This splice-site mutation may be responsible for HHD in this family. This study would further expand the mutation spectrum of the ATP2C1 gene and may be helpful in the genetic counseling and prenatal diagnosis of HHD. K E Y W O R D S ATP2C1 gene, Hailey-Hailey disease (HHD), mutation analysis, Sanger sequencing, splice-site mutation J Cell Biochem. 2019;120:3630-3636. wileyonlinelibrary.com/journal/jcb 3630 |

Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease

“…Novel c.325-3 T > G and recurrent c.1308 + 1G > T mutations also lead to in-frame exons skipping (of exons 5 and 15, respectively). Moreover, given that skipping of exons 5 and 15 due to other mutations have been described before (Kitajima 2002;Matsuda et al 2014;Xiao et al 2019), our observation indicates that despite distinct molecular lesions, the functional effect of mutations may be similar, which could be significant with regard to the purposes of personalized treatment.…”

Review of 52 cases with Hailey–Hailey disease identified 25 novel mutations in Chinese Han population

“…Mutations in ATP2C1 have been implicated in the pathogenesis of HHD. To date, 184 mutations in ATP2C1 have been identified …”

Two Novel ATP2C1 Mutations in Portuguese Patients with Hailey-Hailey Disease

“…Since ATP2C1 was first reported as the causative gene for HHD in 2000, at least 185 ATP2C1 gene mutations have been discovered worldwide. 6 7 They result in conformational defects and decreased levels of hSPCA1, leading to Golgi apparatus fragmentation, impaired cell proliferation, and defective sorting of proteins. 6 No clear correlation between the genotype and phenotype was reported so far.…”

“…6 7 They result in conformational defects and decreased levels of hSPCA1, leading to Golgi apparatus fragmentation, impaired cell proliferation, and defective sorting of proteins. 6 No clear correlation between the genotype and phenotype was reported so far. 7,8 Age of onset, severity, or progression could not be attributed to the mutation location or type in the putative protein structure.8 Modifying genes and environmental factors may greatly influence clinical features of the disease.…”