the Cu-ATPase must enter into the secretory pathway by first moving from the endoplasmic reticulum to the Golgi (Francis et al. 1998). Because the error was not observed in all the mRNAs, the individual had the capacity to synthesize an intact Cu-ATPase, but at a reduced level. The observation might explain why OHS is a considered a mild as opposed to a debilitating form of Menkes disease.

Tissues from mottled mutants bearing the blotchy allele display two large sized mRNAs, demonstrating a likely defect in splicing (Mercer et al. 1993). Levinson et al. (1996) showed that the splice-site mutation in the blotchy allele is identical to that seen in mRNA from Menkes patients.

Wilson disease, or hepatolenticular degeneration, is an autosomal recessive disorder that results from accumulation of copper predominantly in the liver and brain (Bush et al. 1955; Strickland et al. 1969; O'Reilly et al. 1971; Frommer 1974; Gibbs and Walshe 1980). The accumulation is due to defective biliary excretion of copper. Current data indicate that adult humans need to ingest about 0.75 mg of copper daily to sustain a balance (Brewer and Yuzbasiyan-Gurkan 1992). Typically, humans ingest about 1 mg of copper per day (Holden et al. 1979; Klevay et al. 1979; Reiser et al. 1985; Hill et al. 1987; Iyengar et al. 1988; Milne 1998; Brewer and Yuzbasiyan-Gurkan 1992). The daily excess of copper averaging about 0.25 mg per day is normally excreted in the feces (Brewer and Yuzbasiyan-Gurkan 1992). However, due to a genetic defect, individuals with Wilson disease are unable to excrete the excess copper, resulting in a gradual build-up of copper in the body (Bush et al. 1955; Frommer 1974; O'Reilly et al. 1971; Strickland et al. 1969; Gibbs and Walshe 1980).

Clinically, Wilson patients begin receiving medical attention because of hepatic, neurological, or psychiatric symptoms, in roughly equal proportions (Brewer and Yuzbasiyan-Gurkan 1992; Scheinberg and Sternlieb 1984). Some individuals with Wilson disease are diagnosed before the appearance of clinical symptoms through the screening of Wilson disease siblings, who are at a 25% risk for the disease (Brewer and Yuzbasiyan-Gurkan 1992; Scheinberg and Sternlieb 1984). Wilson patients have underlying liver cirrhosis at the time of diagnosis, even if the symptoms are subclinical (Brewer and Yuzbasiyan-Gurkan 1992).

The primary genetic defect in Wilson disease is in ATP7B, which encodes a copper transport protein (Bull et al. 1993; Tanzi et al. 1993; Yamaguchi et al. 1993). The normal mechanism for biliary excretion of copper and the role of the ATP7B gene product in that excretion have yet to be elucidated. It has been hypothesized that ceruloplasmin plays a role