A NOVEL MISSENSE MUTATION OF THE TISSUE-NONSPECIFIC ALKALINE-PHOSPHATASE GENE DETECTED IN A PATIENT WITH HYPOPHOSPHATASIA

Hypophosphatasia is a rare heritable inborn error of metabolism charac terized by abnormal bone mineralization associated with a deficiency o f alkaline phosphatase. The clinical expression of hypophosphatasia is highly variable, ranging from death in utero to pathologic fractures first presenting in adulthood. We investigated the tissue-nonspecific alkaline phosphatase (TNSALP) gene from a Japanese female patient with hypophosphatasia. By a quantitative polymerase chain reaction (PCR) m ethod, the amount of TNSALP mRNA appeared to be almost equal to that i n normal individuals. Gene analysis clarified that the hypophosphatasi a originated from a missense mutation and a nucleotide deletion. The m issense mutation, a C --> T transition at position 1041 of cDNA, resul ts in an amino acid change from Leu to Phe at codon 272, which has not yet been reported. The previously reported deletion of T at 1735 caus es a frame shift mutation downstream from Leu at codon 503. Family ana lysis showed that the mutation 1041T and the deletion 1735T had been i nherited from the proband's father and mother, respectively. An expres sion experiment revealed that the mutation 1041T halved the expression of alkaline phosphatase activity. Using homology analysis, the Leu-27 2 was confirmed to be highly con served in other mammals.