Abstract
Copper (Cu) is an indispensable metal for normal development and function of humans, especially in central nervous system (CNS). However, its redox activity requires accurate Cu transport system. ATP7A, a main Cu2+ transporting-ATPase, is necessary to efflux Cu across the plasma membrane and synthesize cuproenzymes. Menkes disease (MD) is caused by mutations in ATP7A gene. Clinically, MD is Cu deficiency syndrome and is treated with Cu-histidine injections soon after definite diagnosis. But outcome of the most remains poor. To estimate the standard therapy, Cu distribution in the treated classic MD patients is analyzed by synchrotron-generated X-ray fluorescence technique (SR-XRF), which identifies and quantifies an individual atom up to at subcellular level of resolution with wide detection area. SR-XRF analysis newly reveals that Cu exists in spinal cord parenchyma and flows out via venous and lymph systems. By systemic analysis, excess Cu is detected in the proximal tubular cells of the kidney, the mucosal epithelial cells of the intestine, and the lymph and venous systems. The current study suggests that the standard therapy supply almost enough Cu for patient tissues. But given Cu passes through the tissues to venous and lymph systems, or accumulate in the cells responsible for Cu absorption.
Highlights
Menkes disease (MD) is an X-linked recessive disorder, caused by mutation in the Cu-transporting ATPase gene (ATP7A)[1,2]
Because Cu ion is toxic with the redox activity simultaneously, it exists in organisms as a complex with a series
We check the cellular Cu export ability of dermal keratinocyte cultures derived from our MD patient and the unaffected control same as mutational analysis
Summary
Menkes disease (MD) is an X-linked recessive disorder, caused by mutation in the Cu-transporting ATPase gene (ATP7A)[1,2]. The ATP7A protein is a transmembrane P-type ATPase that binds Cu(I) delivered by Cu chaperons such as Atox 1, and translocates Cu within the trans-Golgi network (TGN) to incorporate it into cuproenzymes, or efflux Cu across the plasma membrane to maintain cellular Cu homeostasis[2]. MD is Cu deficiency syndrome by featured the dysfunction of multiple Cu-dependent enzymes. One of the clear etiologies is malabsorption of Cu from intestinal tract[1,3]. At the onset of symptoms, the MD patients’ laboratory data show low levels of serum Cu and ceruloplasmin. Histidine-Cu injections immediately normalizes their levels[3,4,5]. To clarify the results of the standard therapy, we analyzed the Cu status using core-shell electron-generated X-ray fluorescence (XRF), which is counted by the number of photons at atomic number specific X-ray frequency according to Moseley’s law[8]
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