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

M Micaroni,G G Xiao,L Federici,R Plebani,G Giacchetti

doi:10.1038/cddis.2016.147

M Micaroni, G G Xiao + Show 3 more

Open Access

https://doi.org/10.1038/cddis.2016.147

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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.

Highlights

The C-terminal tails of two out of four secretory pathway Ca2+-ATPase pump type 1 (SPCA1) isoforms display a sequence motif recognized by PDZ domains, potentially used to interact with different pools of protein and involved in different signaling pathways
SPCA1 has important roles in regulating membrane trafficking, as a Ca2+ pump able to trigger the Ca2+ influx into the lumen of the golgi apparatus, but it has a direct role in organizing cargo maturation/delivery from the golgi apparatus, which is imbalanced in cancer and other diseases
Why mutations on the ATP2C1 gene cause a different etiology between human and mouse? Does the overlap of ATP2C1 gene with ASTE1 gene have a role in regulating the SPCA1 expression in a different manner between species?

Summary

D2 a 1 b

Hs-SPCA1a DLLFLLGLTSSVCIVAEIIKKVERSREKIQKHVSSTSS--SFLEV Hs-SPCA1b DLLFLLGLTSSVCIVAEIIKKVERSREKIQKHVWLWERSGQQLVEIHPHLETGLPLTEDVSCV Hs-SPCA1c GLALGEEWTAAG Hs-SPCA1d DLLFLLGLTSSVCIVAEIIKKVERSREKIQKHVSSTSS--SFLEVWLWERSGQQLVEIHPHLETGLPLTEDVSCV. Mutations are scattered along the ATP2C1 gene without apparent clustering, showing a substantial allelic heterogeneity, and are distributed all over the encoded sequence (Supplementary Figure 1), as well as in the intron splice sites generating alternative splicing and/or truncated proteins. Mutations affect all domains of the resulting protein.

ATG aag gtt gca cgt ttt caa aaa ata cct aat ggt gaa aat gag aca atg at t

91 AVISVLMHQFDDAVSITV

Findings

Conclusions