Overlapping ATP2C1 and ASTE1 Genes in Human Genome: Implications for SPCA1 Expression?

Massimo Micaroni,Lorenzo Malquori

doi:10.3390/ijms14010674

Abstract

The ATP2C1 gene encodes for the secretory pathway calcium (Ca2+)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca2+-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation.

Highlights

The human ATP2C1 gene transcript, encoding for the secretory pathway calcium (Ca2+)-ATPase pump type 1 (SPCA1), is alternatively spliced
The terminal exon of the human ATP2C1 gene overlaps with the ASTE1 gene on the opposing strand and whose open reading frame is transcribed towards ATP2C1 (Figure 1C) [3]
We hypothesize that human ATP2C1 gene expression is influenced by an overlapping ASTE1 gene

Summary

Introduction

The human ATP2C1 gene transcript, encoding for the secretory pathway calcium (Ca2+)-ATPase pump type 1 (SPCA1), is alternatively spliced. There has been some confusion about the various splice variants, Fairclough et al presented a unifying study describing four isoforms [1]. The terminal exon of the human ATP2C1 gene overlaps with the ASTE1 gene on the opposing strand and whose open reading frame is transcribed towards ATP2C1 (Figure 1C) [3]. This transcriptional overlap is not present in the mouse genome (Figure 1D), according to the present literature and experimental data [4], where no alternative splicing has been detected so far. The ASTE1 open reading frame is oriented in the opposite direction with respect to that of ATP2C1 in both genomes

Mutations in ATP2C1 Cause Hailey-Hailey Disease in Humans but not Mice

ASTE1 may Influence Expression of ATP2C1 Isoforms

Findings

Conclusions