Asp361Val Mutant of Alkaline Phosphatase Found in Patients with Dominantly Inherited Hypophosphatasia Inhibits the Activity of the Wild-Type Enzyme

• DOI: 10.1210/jcem.85.2.6373
• Publication Date: 2014-01-08T17:05:11Z
• Authors: Hermann L. Müller; Miwa Yamazaki; Toshimi Michigami; Takashi Kageyama; Eckhard Schönau; Peter Schneider; Keiichi Ozono
• Keywords: Hypophosphatasia; Wild type; Mutant protein

Hypophosphatasia is characterized by the hypomineralization of bone associated with mutation tissue-nonspecific alkaline phosphatase (TNSALP) gene. Although disease usually autosomal recessive, an dominant form also recognized. Approximately 50 mutations have been found in TNSALP gene patients hypophosphatasia. However, identified to date do not seem account for dominantly inherited disease. We examined a German family which father and all 4 children were affected hypophosphatasia, whereas mother was healthy. The members this showed premature loss deciduous teeth at or shortly before 2 yr age low levels serum ALP elevated urinary phosphoethanolamine. DNA analysis direct sequencing revealed heterozygous missense that caused conversion amino acid Asp Val position 361 (D361V) patients. Another substitution detected exon 12 (Val Ala codon 505: V505A) 1 allele 3 children, indicating no association Reconstruction experiments demonstrated D361V mutant protein lost its enzymatic activity it inhibited function wild-type enzyme when coexpressed COS-7 cells. On other hand, V505A exhibited activities equal those ALP. It likely forms dimers protein, protein-protein interaction contributes effect D361V. causes first one proven be