Abstract
In humans, deficiency of the tissue non-specific alkaline phosphatase (TNAP) gene is associated with defective skeletal mineralization. In contrast, 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 pyridoxal 5'-phosphate (PLP), characterized by elevated serum PLP levels, results in reduced levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The mutant seizure phenotype can be rescued by the administration of pyridoxal and a semi-solid diet. Rescued animals subsequently develop defective dentition. This study reveals essential physiological functions of TNAP in the mouse.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaline Phosphatase / deficiency*
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Alkaline Phosphatase / genetics
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Alkaline Phosphatase / physiology
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Animals
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Brain Chemistry
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Calcification, Physiologic / genetics
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Disease Models, Animal
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Epilepsy / genetics*
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Genes, Lethal*
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Humans
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Hypophosphatasia / genetics
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Mice
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Mice, Neurologic Mutants
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Paralysis / chemically induced
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Phenotype
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Pyridoxal Phosphate / blood
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Pyridoxal Phosphate / therapeutic use
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Pyridoxal Phosphate / toxicity
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Species Specificity
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Tooth Abnormalities / genetics
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Vitamin B 6 Deficiency / diet therapy
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Vitamin B 6 Deficiency / drug therapy
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Vitamin B 6 Deficiency / genetics*
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gamma-Aminobutyric Acid / deficiency*
Substances
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gamma-Aminobutyric Acid
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Pyridoxal Phosphate
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Alkaline Phosphatase