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Title: Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes.

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

Published In J Biol Chem, (2007 Sep 07)

Abstract: Loss of one copy of the human ATP2C1 gene, encoding SPCA1 (secretory pathway Ca(2+)-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 Ca(2+) 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 Ca(2+) pump causes Golgi stress, expansion of the Golgi, increased apoptosis, and embryonic lethality and demonstrates that SPCA1 haploinsufficiency causes a genetic predisposition to cancer.

PubMed ID: 17597066 Exiting the NIEHS site

MeSH Terms: Aging/genetics; Aging/metabolism; Aging/pathology; Animals; Apoptosis/genetics; Basement Membrane/metabolism; Basement Membrane/ultrastructure; Calcium-Transporting ATPases/deficiency*; Calcium-Transporting ATPases/metabolism; Carcinoma, Squamous Cell/genetics; Carcinoma, Squamous Cell/metabolism*; Carcinoma, Squamous Cell/pathology; Cardiovascular System/embryology; Coated Pits, Cell-Membrane/genetics; Coated Pits, Cell-Membrane/metabolism; Coated Pits, Cell-Membrane/ultrastructure; Desmosomes/genetics; Desmosomes/metabolism; Desmosomes/ultrastructure; Embryo Loss/genetics; Embryo Loss/metabolism*; Embryo Loss/pathology; Endoplasmic Reticulum, Rough/genetics; Endoplasmic Reticulum, Rough/metabolism; Endoplasmic Reticulum, Rough/ultrastructure; Esophageal Neoplasms/genetics; Esophageal Neoplasms/metabolism*; Esophageal Neoplasms/pathology; Female; Genetic Predisposition to Disease; Golgi Apparatus/metabolism*; Golgi Apparatus/ultrastructure; Hematopoiesis/genetics; Heterozygote; Homozygote; Humans; Inbreeding; Loss of Heterozygosity*/genetics; Male; Mice; Mice, Knockout; Neural Tube Defects/embryology; Neural Tube Defects/metabolism; Neural Tube Defects/pathology; Pemphigus, Benign Familial/genetics; Pemphigus, Benign Familial/metabolism; Pemphigus, Benign Familial/pathology; Pregnancy; Protein Transport/genetics; Ribosomes/metabolism; Secretory Vesicles/genetics; Secretory Vesicles/metabolism; Secretory Vesicles/ultrastructure; Skin Neoplasms/genetics; Skin Neoplasms/metabolism*; Skin Neoplasms/pathology; Water-Electrolyte Balance/genetics

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Last Reviewed: October 07, 2024