Waymire K G, Mahuren J D, Jaje J M, Guilarte T R, Coburn S P, MacGregor G R
Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nat Genet. 1995 Sep;11(1):45-51. doi: 10.1038/ng0995-45.
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.
在人类中，组织非特异性碱性磷酸酶（TNAP）基因的缺陷与骨骼矿化缺陷有关。相比之下，利用胚胎干细胞（ES）通过同源重组产生的缺乏TNAP的小鼠具有正常的骨骼发育。然而，在出生后约两周，纯合突变小鼠会出现癫痫发作，随后死亡。以血清PLP水平升高为特征的磷酸吡哆醛（PLP）代谢缺陷，导致大脑中抑制性神经递质γ-氨基丁酸（GABA）水平降低。通过给予吡哆醛和半固体饮食可以挽救突变的癫痫发作表型。获救的动物随后会出现牙列缺陷。这项研究揭示了TNAP在小鼠中的重要生理功能。
