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Table 2 Table 2

From: Hypophosphatasia

Class Cell localization Degradation, other features 3D model localization Mutation and reference AP activity (% wild type)
1 Intracellular accumulation; fails to move beyond the cis-Golgi Degradation in the proteasome Functional domains (homodimer interface, calcium binding site, active site) R54C (c.211C>T), [29] 0
     N153D (c.508A>G) [32] 0
     I201T (c.653T>C) [40] 0
     E218G (c.704A>G) [19]; [26] 0
     D277A (c.881A>C) [29] 0
     D289V (c.917A>T) [33] 0
     G317D (c.1001G>A) [25] 0
2 Intracellular accumulation; fails to move beyond the cis-Golgi Degradation in the proteasome Not localized in a particular domain A162T (c.535G>A) [26]; [29] 18
     G232V (c.746G>T) [40] 34
3 Cell membrane and cytoplasme   Not localized in a particular domain F310L c.979T>C [28] 72
     E174K (c.571G>A) [40] 88
     I473F (c.1468A>T) [40] 37
    Active site vicinity G438S (c.1363G>A) [40] 71
4 Cell membrane   Not localized in a particular domain A115V (c.395C>T) [34] 17
  Intracellular localization; absence on cell surface Large-sized secretory protein lacking GPI; aggregation due to disulphide bonds beween new cystein residues   c.1559delT [35] 28
  Cell membrane Disulphide bond between new cystein residues Crown domain R433C (c.1348C>T) [39] 4
  1. Attempt to classify the ALPL gene mutations according to site-directed mutagenesis, in vitro alkaline phosphatase activity assays, and cell localization by immunofluorescence. Only mutations studied for all these parameters are shown. Class 1 represents the most severe mutations resulting in mutant proteins accumulated in the cytoplasm, subsequently degraded, and therefore producing no in vitro residual activity. These mutations affect residues of functional domains of the enzyme and were mostly found in patients with severe hypophosphatasia. Mutations of class 2 are also accumulated in the cell but exhibit low but significant in vitro residual activity and could be therefore degraded with delay. These mutations, that do not affect particular functional domains of the protein, must be also considered as severe alleles. Mutations of class 3 are in part accumulated in the cytoplasm but also in part reach the cell membrane. They exhibit high in vitro residual activity and except G438S, do not affect residues of functional domains. These mutations are observed in patients with mild forms of hypophosphatasia. Class 4 regroups particular mutations not assignable to the above classes.
  2. Nucleotides numbering is given according to [77] and the Nomenclature Working Group [78]: the first nucleotide (+1) corresponds to the A of the ATG initiation codon. Amino acids numbering is given according to a non-standardized nomenclature [77] taking into account of a 17-residues signal peptide,i.e. the ATG initiation codon is numbered as residue minus (-)17.