Abstract
The dominant negative effect of mutations is rare in metabolic diseases and its mechanism has not been studied much. Hypophosphatasia, a bone inherited metabolic disorder, is a good model because the disease can be dominantly transmitted. The gene product activity depends on a homodimeric configuration and many mutations have been reported in the ALPL gene responsible for the disease. Using CFP/YFP-tagged-TNSALP plasmids, transfections in COS cells and confocal fluorescence analyses, we studied the point mutation G232V (c.746G>T). We showed that the G232V protein sequestrates some of the wild-type protein into the cells and prevents it from reaching the membrane where it plays its physiological role.
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Acknowledgments
This work was supported by a grant from the Université de Versailles-Saint Quentin (J.L.S., E.M.) and from the Institut de Recherches Internationales Servier (J.L.S.).
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A. S. Lia-Baldini and I. Brun-Heath equally contributed to this work.
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Lia-Baldini, A.S., Brun-Heath, I., Carrion, C. et al. A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein . Hum Genet 123, 429–432 (2008). https://doi.org/10.1007/s00439-008-0480-1
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DOI: https://doi.org/10.1007/s00439-008-0480-1