Somatic Mosaicism in Menkes Disease Suggests Choroid Plexus-Mediated Copper Transport to the Developing Brain
Somatic Mosaicism in Menkes Disease Suggests Choroid Plexus-Mediated Copper Transport to the Developing Brain
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DOI：
10.1002/ajmg.a.33632
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发表时间：
2010-10-01
影响因子：
2
通讯作者：
Kaler, Stephen G.
中科院分区：
文献类型：
--
作者：
Donsante, Anthony;Johnson, Paul;Kaler, Stephen G.
铜向大脑运输的主要机制尚不清楚，尽管这一过程在门克斯病中严重受损，这是一种X连锁的神经发育障碍，由进化上保守的铜转运蛋白ATP7A突变引起。铜进入中枢神经系统的可能途径包括起源于中胚层血管母细胞并形成血脑屏障的脑毛细血管内皮细胞，以及源自胚胎外胚层并形成血脑脊液屏障的脉络丛。我们利用了一个罕见的(也是首次报道的)体细胞嵌合体ATP7A突变的例子来阐明铜进入发育中的大脑的问题。在一名20个月大的门克斯病患者中，在铜治疗前进行评估，血铜和儿茶酚胺浓度正常，而脑脊液中的浓度异常，与他的神经学严重表型一致。我们记录了来自不同胚胎来源的组织中不同水平的ATP7A错义突变P1001L的嵌合体；等位基因定量显示，大约27%的血细胞DNA样本(来自中胚层)和88%来自培养的成纤维细胞(来自外胚层)的DNA样本中存在P1001L。这些发现表明，患者的P1001L突变先于原肠胚形成三个初级胚胎谱系，外胚层最终拥有比中胚层或内胚层更高比例的突变细胞。由于脉络丛上皮细胞来源于神经外胚层，而脑毛细血管内皮细胞来源于中胚层血管母细胞，因此该婴儿的临床和生化研究结果支持血脑脊液屏障(脉络丛上皮细胞)在铜进入发育中的大脑中起关键作用。出版(C)2010年Wiley-Liss，Inc.(Dagger)
The primary mechanism of copper transport to the brain is unknown, although this process is drastically impaired in Menkes disease, an X-linked neurodevelopmental disorder caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Potential central nervous system entry routes for copper include brain capillary endothelial cells that originate from mesodermal angioblasts and form the blood-brain barrier, and the choroid plexuses, which derive from embryonic ectoderm, and form the blood-cerebrospinal fluid barrier. We exploited a rare (and first reported) example of somatic mosaicism for an ATP7A mutation to shed light on questions about copper transport into the developing brain. In a 20-month-old Menkes disease patient evaluated before copper treatment, blood copper, and catecholamine concentrations were normal, whereas levels in cerebrospinal fluid were abnormal and consistent with his neurologically severe phenotype. We documented disparate levels of mosaicism for an ATP7A missense mutation, P1001L, in tissues derived from different embryonic origins; allele quantitation showed P1001L in approximately 27% of DNA samples from blood cells (mesoderm-derived) and 88% from cultured fibroblasts (ectoderm-derived). These findings imply that the P1001L mutation in the patient preceded formation of the three primary embryonic lineages at gastrulation, with the ectoderm layer ultimately harboring a higher percentage of mutation-bearing cells than mesoderm or endoderm. Since choroid plexus epithelia are derived from neuroectoderm, and brain capillary endothelial cells from mesodermal angioblasts, the clinical and biochemical findings in this infant support a critical role for the blood-CSF barrier (choroid plexus epithelia) in copper entry to the developing brain. Published (C) 2010 Wiley-Liss, Inc.(dagger)