title: A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein.
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.
authors.affiliation: EA 4021, Biomolécules et thérapies antitumorales, CHU de Limoges, Limoges, France.
authors.forename: A S
authors.initials: AS
authors.lastname: Lia-Baldini
authors.forename: I
authors.initials: I
authors.lastname: Brun-Heath
authors.forename: C
authors.initials: C
authors.lastname: Carrion
authors.forename: B
authors.initials: B
authors.lastname: Simon-Bouy
authors.forename: J L
authors.initials: JL
authors.lastname: Serre
authors.forename: M E
authors.initials: ME
authors.lastname: Nunes
authors.forename: E
authors.initials: E
authors.lastname: Mornet
mesh_terms: D000469:Alkaline Phosphatase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000201:enzymology* / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008164:Luminescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D020125:Mutation, Missense; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D014162:Transfection
chemical_list: D001426:Bacterial Proteins; C485182:Cyan Fluorescent Protein; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D000469:Alkaline Phosphatase