Indian childhood cirrhosis (ICC) is a fatal liver disease characterize
d by the accumulation of copper-sulfur aggregates. We demonstrated tha
t cultured fibroblasts from a patient with ICC contain vesicular aggre
gates, fibrillar whorls, and crystalloids along with dilated rough end
oplasmic reticulum filled with flocculent material. Although the coppe
r content of the fibroblasts was normal, both basal and metal-induced
metallothionein (MT) synthesis was reduced in the ICC cells. The lower
MT synthesis in ICC cells was seen at copper concentrations of 100, 2
00, and 400 mu M, zinc concentrations of 50 and 100 mu M, and a cadmiu
m concentration of 2 mu M. The lower MT synthesis in ICC cells was not
due to failure of the cells to take up copper because Cu-67 uptake ki
netics were normal is the mutant cells. MT degradation was also normal
in the ICC cells. The size of human MT IIA mRNA was normal in the ICC
cells, but its amount was reduced under both basal and metal-induced
conditions. The MT IIA gene, which is the predominant MT gene in human
beings, showed no sequence alterations in any of its exons, introns,
or promoter region in the ICC cells compared with normal cells. These
studies demonstrate that this case of ICC represents a genetic disease
with some level of expression in cultured fibroblasts; the basic defe
ct may involve insufficient MT mRNA and protein-synthesis for the copp
er load present. However, it remains to be determined whether reduced
MT synthesis is a primary or secondary phenomenon.