X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation Journal Article
| Authors: | Keller, P.; Tremml, G.; Rosti, V.; Bessler, M. |
| Article Title: | X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation |
| Abstract: | A somatic mutation in the X linked PIGA gene is responsible for the deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria. No inherited form of GPI-anchor deficiency has been described. Because conventional Piga gene knockout is associated with high embryonic lethality in chimeric mice, we used the Cre/loxP system. We generated mice in which two loxP sites flank part of Piga exon 2. After crossbreeding with female mice of the EIIa-cre strain, the floxed allele undergoes Cre-mediated recombination with high efficiency during early embryonic development. Because of X chromosome inactivation, female offspring are mosaic for cells that express or lack GPI- linked proteins. Analysis of mosaic mice showed that in heart, lung, kidney, brain, and liver, mainly wild-type Piga is active, suggesting that these tissues require GPI-linked proteins. The salient exceptions were spleen, thymus, and red blood cells, which had almost equal numbers of cells expressing the wild-type or the recombined allele, implying that GPI-linked proteins are not essential for the derivation of these tissues. PIGA(-) cells had no growth advantage, suggesting that other factors are needed for their clonal dominance in patients with paroxysmal nocturnal hemoglobinuria. |
| Keywords: | gene mutation; somatic mutation; gene deletion; nonhuman; animal cell; mouse; animals; mice; mice, knockout; somatic cell; gene expression; animal experiment; animal model; membrane proteins; animalia; gene expression regulation; organ specificity; x chromosome; dosage compensation, genetic; gene inactivation; cre; rodentia; lethality; paroxysmal nocturnal hemoglobinuria; hemoglobinuria, paroxysmal; knockout gene; southern blotting; cross breeding; x chromosome linkage; glycosylphosphatidylinositols; female; priority journal; article; glycosyl phosphatidylinositol; loxp; xp22 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 96 |
| Issue: | 13 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1999-06-01 |
| Start Page: | 7479 |
| End Page: | 7483 |
| Language: | English |
| DOI: | 10.1073/pnas.96.13.7479 |
| PUBMED: | 10377440 |
| PROVIDER: | scopus |
| PMCID: | PMC22111 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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