Molecular studies of ceruloplasmin deficiency in Wilson's disease.

Abstract

Deficiency of serum ceruloplasmin is a characteristic biochemical abnormality of Wilson's disease, although the mechanism of this finding is unknown. Ceruloplasmin messenger RNA (mRNA) levels were therefore examined in five patients with Wilson's disease and five controls with other types of hepatic disease. Northern and dot blot hybridizations showed that detectable ceruloplasmin mRNA was present in all of the patients with Wilson's disease, including one patient with no detectable serum ceruloplasmin. However, the ceruloplasmin mRNA levels in the Wilson's disease patients were only 33% that of controls (P < 0.001). In contrast, albumin mRNA levels in the Wilson's disease patients averaged 161% that of controls. In an attempt to better delineate the level of gene expression responsible for this decrease in ceruloplasmin mRNA, the nuclear run-on assay was used to analyze transcriptional rates. The amount of ceruloplasmin gene transcription in four Wilson's patients was decreased to 44% that of three controls. These results indicate that the diminished serum ceruloplasmin levels in patients with Wilson's disease are due at least in part to a decrease in ceruloplasmin gene transcription.

Perspectives on Wilson's disease

“…Nonetheless, the intriguing association between ceruloplasmin deficiency and Wilson's disease raises interesting questions regarding the level of interaction of the two genes. Czaja et al (13) found that both ceruloplasmin steady-state mRNA and the rate of gene transcription were reduced in patients with Wilson's disease, compared with controls, but not in proportion to the severity of the patients' ceruloplasmin deficiency. A reduced rate of transcription may be due to the action of a hitherto unidentified transacting factor affecting the ceruloplasmin regulatory area.…”

Defective biliary copper excretion in Wilson's disease: the role of caeruloplasmin

“…Previous molecular studies of caeruloplasmin deficiency in Wilson's disease have shown that steady-state levels of caeruloplasmin mRNA are reduced to around one-third of those observed in normal controls, and that this reduction is entirely accounted for by a reduced rate of gene transcription [36]. It thus appears that regulation of hepatic caeruloplasmin secretion in Wilson's disease is under some degree of control at the transcriptional level.…”

“…In the light of the recent identification of the Wilson's disease gene, however, it seems likely that this represents a secondary phenomenon. Thus, while reduced secretion of caeruloplasmin may result from impaired copper incorporation, the observed reduction in transcription could be caused by some form of negative feedback, acting as a mechanism to prevent accumulation of non-secreted protein within ROLE OF BILIARY CAERULOPLASMIN IN WILSON S DISEASE 899 the hepatocyte [36]. This transcriptional control may act in concert with increased turnover of the nascent protein.…”

Nontransplant options for the treatment of metabolic liver disease: Saving livers while saving lives

“…There is relentless accumulation of hepatic copper until the retention capacity is exceeded; copper then escapes the liver to cause damage to other organs (brain and kidneys) and to accumulate in Descemet's membrane in the cornea, visible as Kayser-Fleischer rings. Copper toxicosis may manifest as predominantly hepatic, neurologicallpsychiatric or ophthalmological hsease (12)(13)(14). Hepatic disease occurs in two phenotypes: (a) insidious disease, resembling chronic active hepatitis or cirrhosis, with ultimate decompensation or (b) rapidly progressive, dramatic disease, resembling fulminant liver failure IFLF).…”