Loss of the Atp2c1 Secretory Pathway Ca2+-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes

Gbolahan W. Okunade, Marian L. Miller, Mohamad Azhar, Anastasia Andringa, L. Philip Sanford, Thomas C Doetschman, Vikram Prasad, Gary E. Shull

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Abstract

Loss of one copy of the human ATP2C1 gene, encoding SPCA1 (secretory pathway Ca2+-ATPase isoform 1), causes Hailey-Hailey disease, a skin disorder. We performed targeted mutagenesis of the Atp2c1 gene in mice to analyze the functions of this Golgi membrane Ca2+ pump. Breeding of heterozygous mutants yielded a normal Mendelian ratio among embryos on gestation day 9.5; however, null mutant (Spca1-/-) embryos exhibited growth retardation and did not survive beyond gestation day 10.5. Spca1-/- embryos had an open rostral neural tube, but hematopoiesis and cardiovascular development were ostensibly normal. Golgi membranes of Spca1-/- embryos were dilated, had fewer stacked leaflets, and were expanded in amount, consistent with increased Golgi biogenesis. The number of Golgi-associated vesicles was also increased, and rough endoplasmic reticulum had fewer ribosomes. Coated pits, junctional complexes, desmosomes, and basement membranes appeared normal in mutant embryos, indicating that processing and trafficking of proteins in the secretory pathway was not massively impaired. However, apoptosis was increased, possibly the result of secretory pathway stress, and a large increase in cytoplasmic lipid was observed in mutant embryos, consistent with impaired handling of lipid by the Golgi. Adult heterozygous mice appeared normal and exhibited no evidence of Hailey-Hailey disease; however, aged heterozygotes had an increased incidence of squamous cell tumors of keratinized epithelial cells of the skin and esophagus. These data show that loss of the Golgi Ca2+ pump causes Golgi stress, expansion of the Golgi, increased apoptosis, and embryonic lethality and demonstrates that SPCA1 haploinsufficiency causes a genetic predisposition to cancer.

Original languageEnglish (US)
Pages (from-to)26517-26527
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number36
DOIs
Publication statusPublished - Sep 7 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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