Molecular basis of the brindled mouse mutant (Mo-br): A murine model of Menkes disease
Molecular basis of the brindled mouse mutant (Mo-br): A murine model of Menkes disease
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DOI：
10.1093/hmg/6.7.1037
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发表时间：
1997-07-01
影响因子：
3.5
通讯作者：
Mercer, JFB
中科院分区：
文献类型：
--
作者：
Grimes, A;Hearn, CJ;Mercer, JFB
斑纹小鼠突变体（Mo-br）是最接近人类遗传铜缺乏症门克斯病的动物模型，推测是由于X连锁斑驳位点（Mo）的突变所致。突变小鼠色素减退，在出生后15天左右死亡，但可以在出生后第10天之前通过铜治疗来挽救。门克斯病已被证明是由于编码P型的基因ATP7A突变所致ATP酶（此处称为MNK），MNK很可能在铜从细胞流出中发挥作用，但其全部生物活性尚未完全了解。斑纹小鼠突变的性质对于我们理解 MNK 的作用和设计门克斯病的治疗策略非常重要。在这里，我们表明斑纹小鼠在 Mnk 的一个高度保守但功能上未表征的区域中删除了两个氨基酸。与 Ca ATP 酶的比较表明该区域可能涉及与 E1/E2 转变相关的构象变化，而 E1/E2 转变是 P 型 ATP 酶的作用的基础。我们还描述了组织中 Mnk 的第一个蛋白质印迹数据，这些数据显示突变体和花斑肾中 Mnk 水平正常，但肝脏中没有。在肾脏中，免疫组织化学证明 Mnk 在近端和远端肾小管中，突变体和正常中的分布是相同的，这种分布与 Mnk 参与尿液中的铜重吸收一致。
The brindled mouse mutant (Mo-br) is the closest animal model of the human genetic copper deficiency, Menkes disease, which is presumed to be due to a mutation at the X-linked mottled locus (Mo), The mutant mice are hypopigmented and die at around 15 days after birth, but can be saved by treatment with copper before the 10th postnatal day, Menkes disease has been shown to be due to mutations of the gene ATP7A which encodes P-type ATPase (referred to here as MNK), MNK is likely to function in copper efflux from cells, but the full range of its biological activity is not fully understood. The nature of the mutation in the brindled mouse is of importance in our understanding of the role of MNK and for devising treatment strategies for Menkes disease, Here we show that the brindled mouse has a deletion of two amino acids in a highly conserved, but functionally uncharacterized, region of Mnk, Comparison with the Ca ATPases suggests this region may be involved in conformational changes associated with the E1/E2 transition fundamental to the action of P-type ATPases, We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver, In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal, This distribution is consistent with Mnk being involved in copper resorption from the urine.