ATP2C1 gene mutations in Hailey–Hailey disease and possible roles of SPCA1 isoforms in membrane trafficking

Abstract

ATP2C1 gene codes for the secretory pathway Ca2+/Mn2+-ATPase pump type 1 (SPCA1) localizing at the golgi apparatus. Mutations on the human ATP2C1 gene, causing decreased levels of the SPCA1 expression, have been identified as the cause of the Hailey–Hailey disease, a rare skin disorder. In the last few years, several mutations have been described, and here we summarize how they are distributed along the gene and how missense mutations affect protein expression. SPCA1 is expressed in four different isoforms through alternative splicing of the ATP2C1 gene and none of these isoforms is differentially affected by any of these mutations. However, a better understanding of the tissue specific expression of the isoforms, their localization along the secretory pathway, their specific binding partners and the role of the C-terminal tail making isoforms different from each other, will be future goals of the research in this field.

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

“…Up to now, including the mutations we identified in this study, a total of 209 mutations in ATP2C1 have been found. However, all of them followed a uniform distribution without hotspots or clusters, which is consistent with previous investigations …”

“…However, all of them followed a uniform distribution without hotspots or clusters, which is consistent with previous investigations. 8 Along with our findings, 6.2% (13/209) of mutations were in the N-terminus/S1 domain. The N-terminus contained a Ca 2+binding EF hand-like motif which seemed to regulate ion affinity.…”

“…ATP2C1 encodes the human secretory pathway Ca 2+ /Mn 2+ ‐ATPase protein 1 (SPCA1), which consists of an actuator domain (A), a nucleotide‐binding domain (N), a phosphorylation domain (P) and 10 transmembrane domains (M1–M10) . Thirty‐nine mutations identified in the present study had a dispersed distribution throughout the SPCA1 protein (Fig.…”

“…In 2016, Micaroni et al 8 reviewed all of the reported mutations of HHD since 2000, including 219 independent families and sporadic patients, but failed to find any specific relationships between genotypes and phenotypes. Xu et al 4 summarized all 90 variants in a Chinese Han population.…”

Case of Hailey‐Hailey disease with a novel missense/in‐frame deletion mutation in ATP2C1 successfully treated with cyclosporine

“…SPCA1 consists of actuator, nucleotide-binding, phosphorylation domains, and 10 transmembrane helices. 1 The patient's mutation resides in second transmembrane domain whose interaction with actuator/phosphorylation domains is critical for Ca 2+ release into Golgi, 2 and might be compromised by this mutation.…”