A novel splice‐site mutation in the A TP2C1 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.