FORMATION AND MAINTENANCE OF BONE AND TOOTH - APPROACH THROUGH THE ANALYSTS OF HYPOPHOSPHATASIA

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As a first step to understand the molecular mechanism by. which mutations in the tissue-nonspecific alkaline phosphatase gene (TNSALP) cause hypophosphatasia, we have analyzed the effects of severafmissense mutations on.the properties of TNSALP Analyzed mutants are as follows: TNSALP (R54C), TNSALP (D277A) and TNSALP [N153D] reported in the patients diagnosed with sever form of hypophsophatasia. When being expressed in COS- 1 cells, these mutated form of TNSALP were found to fail to assume proper folding and correct assembly, resulting in the formation of a high-molecular mass aggregate. These aberrant proteins tend to accumulate in the endoplasmic reticulum (TNSALP [R54C]) and cis-Golgi (TNSALP [N153D] en route to the cell surface, followed by degradation in proteasome.