Mice lacking tissue non-specific 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 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.
Waymire
K G
KG
Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Mahuren
J D
JD
Jaje
J M
JM
Guilarte
T R
TR
Coburn
S P
SP
MacGregor
G R
GR
D000469:Alkaline Phosphatase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001923:Brain Chemistry; D002113:Calcification, Physiologic / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics*; D005804:Genes, Lethal; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D010243:Paralysis / Q000139:chemically induced; D010641:Phenotype; D011732:Pyridoxal Phosphate / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D013045:Species Specificity; D014071:Tooth Abnormalities / Q000235:genetics; D026681:Vitamin B 6 Deficiency / Q000178:diet therapy / Q000188:drug therapy / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000172:deficiency*
D005680:gamma-Aminobutyric Acid; D011732:Pyridoxal Phosphate; D000469:Alkaline Phosphatase