MICE LACKING TISSUE NONSPECIFIC ALKALINE-PHOSPHATASE DIE FROM SEIZURES DUE TO DEFECTIVE METABOLISM OF VITAMIN-B-6

In humans, deficiency of the tissue non-specific alkaline phosphatase (TNAP) gene is associated with defective skeletal mineralization. In c ontrast, mice lacking TNAP generated by homologous recombination using embryonic stem (ES) cells have normal skeletal development. However, at approximately two weeks after birth, homozygous mutant mice develop seizures which are subsequently fatal. Defective metabolism of pyrido xal 5'-phosphate (PLP), characterized by elevated serum PLP levels, re sults in reduced levels of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) in the brain. The mutant seizure phenotype can be rescued by the administration of pyridoxal and a semi-solid diet. Resc ued animals subsequently develop defective dentition. This study revea ls essential physiological functions of TNAP in the mouse.