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.
Highlights
(endo)plasmic reticulum Ca2ϩ-ATPases [4], and four plasma membrane Ca2ϩ-ATPases [5, 6]
Limited information is available for the SPCAs [8], which are closely related to PMR1, a P-type Ca2ϩ-ATPase in yeast that is expressed in Golgi membranes [9] and transports both Ca2ϩ and Mn2ϩ [10]
PCR genotyping of tail DNA of live offspring (Fig. 1C) of heterozygous breeding pairs revealed that only wild-type and heterozygous pups, in a 1:2 ratio (228:425), were present at birth, indicating that the homozygous null mutation caused embryonic lethality
Summary
(endo)plasmic reticulum Ca2ϩ-ATPases [4], and four plasma membrane Ca2ϩ-ATPases [5, 6]. HHD is similar to Darier disease, which is caused by null mutations in one copy of the human ATP2A2 gene, encoding SERCA2 [16]. Both diseases are characterized by acantholysis (a disruption of cell-cell contacts) in the suprabasal layers of the skin. A low incidence of squamous cell tumors has been reported in both Darier disease [19] and HHD [20, 21], but it is unclear whether this is a chance association or is caused by the reduction in Ca2ϩ pump levels and activity. The parallels between the effects of SPCA1 deficiency and SERCA2 deficiency are consistent with a model in which species differences in the balance between prosurvival and proapoptotic responses of keratinocytes to secretory pathway stress favor development of cancer in mice and acantholytic skin disease in humans
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