Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R.
Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R.
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DOI：
10.1016/j.ymgme.2008.06.015
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发表时间：
2008-11
影响因子：
3.8
通讯作者：
Kaler, Stephen G.
中科院分区：
文献类型：
--
作者：
Tang, Jingrong;Donsante, Anthony;Desai, Vishal;Patronas, Nicholas;Kaler, Stephen G.
门克斯病是一种致命的婴儿神经退行性疾病，由X-连锁铜运输基因ATP7A缺陷引起。最近一项临床试验的证据表明，对这种疾病的早期注射铜治疗的有利反应涉及保留一些铜运输能力的突变。在三个没有血缘关系的婴儿中，我们在ATP7A基因产物的第二个跨膜片段中发现了相同的突变G727R，该突变补充了酿酒酵母铜运输突变体，与部分铜运输活性一致。定量逆转录-聚合酶链式反应研究表明，与野生型对照相比，两名患者成纤维细胞中ATP7AG727R转录本的水平大致正常，但Western印迹分析显示ATP7A蛋白的数量显著减少，表明翻译后降解。我们通过比较突变体和野生型ATP7A在环己胺处理培养的成纤维细胞中的降解率来证实后者；G727R突变体的半衰期为2.9小时，野生型为11.4小时。我们还记录了G727R细胞中的X-box结合蛋白1剪接变体-已知与细胞错误折叠蛋白反应有关。患者A被诊断为6个月大，在228天(7.6个月)开始治疗。在他现在的年龄(2岁)，他的整体神经发育保持在2到4个月的水平。相比之下，患者B和C在新生儿期被诊断出来，在25天内开始治疗，并在他们当前的年龄，3岁(B)和7个月(C)表现出接近正常的神经发育。具有相同错义突变的患者A与结果接近正常的患者A和B的临床结果不佳，证实了早期医学干预对门克斯病的重要性，并突出了新生儿筛查这种疾病的关键潜在好处。
Menkes disease is a fatal neurodegenerative disorder of infancy caused by defects in an X-linked copper transport gene, ATP7A. Evidence from a recent clinical trial indicates that favorable response to early treatment of this disorder with copper injections involves mutations that retain some copper transport capacity. In three unrelated infants, we identified the same mutation, G727R, in the second transmembrane segment of the ATP7A gene product that complemented a S. cerevisiae copper transport mutant, consistent with partial copper transport activity. Quantitative reverse transcription-polymerase chain reaction studies showed approximately normal levels of ATP7AG727R transcript in two patients’ fibroblasts compared to wild type controls, but Western blot analyses showed markedly reduced quantities of ATP7A protein, suggesting post-translational degradation. We confirmed the latter by comparing degradation rates of mutant and wild type ATP7A via cyclohexamide treatment of cultured fibroblasts; half-life of the G727R mutant was 2.9 hr and for the wild-type, 11.4 hr. We also documented a X-box binding protein 1 splice variant in G727R cells - known to be associated with the cellular misfolded protein response. Patient A, diagnosed 6 months of age, began treatment at 228 days (7.6 mos) of age. At his current age (2 years), his overall neurodevelopment remains at a 2 to 4 month level. In contrast, patients B and C were diagnosed in the neonatal period, began treatment within 25 days of age, and show near normal neurodevelopment at their current ages, 3 years (B), and 7 months (C). The poor clinical outcome in patient A with the same missense mutation as patients A and B with near normal oucomes, confirms the importance of early medical intervention in Menkes disease and highlights the critical potential benefit of newborn screening for this disorder.
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DOI：
10.1006/bmme.1996.0007
发表时间：
1996-02-01
期刊：
BIOCHEMICAL AND MOLECULAR MEDICINE
影响因子：
--
作者：
Kaler, SG;Das, S;Gahl, WA
通讯作者：
Gahl, WA
影响因子：
4.8
作者：
Kim, BE;Smith, K;Petris, MJ
通讯作者：
Petris, MJ
DOI：
10.1016/j.ijporl.2007.02.021
发表时间：
2007-07-01
影响因子：
1.5
作者：
Price, David J.;Ravindranath, Thyyar;Kaler, Stephen G.
通讯作者：
Kaler, Stephen G.
影响因子：
5.1
作者：
Schlief, ML;Gitlin, JD
通讯作者：
Gitlin, JD
影响因子：
5.3
作者：
COOPER, DN;KRAWCZAK, M
通讯作者：
KRAWCZAK, M