OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B(H1069Q), but also viability of Cu-treated human glioblastoma U87 cells.
By utilizing the age at onset, neurological involvement score and ATP7B mutation background, we generated a genotype-phenotype matrix that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective "outliers" to be investigated for their remarkable phenotypic divergence.
Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined.
ATP7B is one of two copper-transporting ATPases in humans, its vital role being manifested in Wilson disease due to a mutation in the gene that encodes this pump.
The gene responsible for WD is located in 13q14.3 chromosome, contains 21 exons and codes for copper specific transporting P-type adenosinetriphosphatase (ATPase) (ATP7B).
The aim of this study was to screen and detect mutations of the ATP7B gene in unrelated Turkish Wilson disease patients (n = 46) and control group (n = 52).
The Drosophila ATP7 copper transporter has sequence homology to the human copper transporters ATP7A and ATP7B, which are defective in Menkes and Wilson disease, respectively.
These examples illustrate how impaired regulation of copper transport pathways can cause organ damage and provide important insights into the impact of defects in specific molecular processes, including those catalyzed by the copper-transporting ATPases, ATP7A (mutated in Menkes disease), ATP7B (Wilson's disease), and the copper chaperones such as those for cytochrome c oxidase, SCO1 and SCO2.
Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway.
In 78 selected patients of the cohort with two mutations in ATP7B, we have examined genotype-phenotype correlation between the detected changes in Atox1 and COMMD1 genes, and the presentation of the WD patients.
Studies in the Atp7b(-/-) mouse model of WD revealed specific transcript and metabolic changes that precede development of liver pathology, most notably downregulation of transcripts in the cholesterol biosynthetic pathway.
The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD.
Previous studies on the mouse model for WD (Atp7b(-)(/-)) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology.