Hiroko Kodama

1. INTRODUCTION

Menkes disease (MNK) is an X-linked recessive disorder characterized by progressive neuronal degeneration and connective tissue abnormalities, first described by Menkes and co-workers in 1962 (1). In 1972, Danks et al. demonstrated that MNK is associated with copper deficiency as a result of a defect in intestinal copper absorption, which results in copper accumulation in the intestine (2,3). This observation, together with the discovery of a mutant strain of mice serving as a model of MNK, mottled mutant mice, led to many studies on copper metabolism and the pathophysiology of this disease (4,5). Moreover, patients with a milder MNK phenotype have been reported. These patients are generally said to have "mild MNK," whereas the typical phenotype is referred to as "classical MNK." In this chapter, classical MNK and mild MNK are referred to as MNK and mild MNK, respectively. Occipital horn syndrome (OHS), first described by Lazoff et al. in 1975 (6), is considered to represent the mildest form of MNK.

In 1993, approx 30 yr after Menkes' original report, the Menkes disease gene was identified as a gene encoding a copper-transporting P-type ATPase (ATP7A) (7-9). Both mild MNK and OHS have been identified as genetic disorders resulting from mutations in the ATP7A gene (10,11). Moreover, mottled mice have been reported to have mutations in the mottled gene (atp7a), the murine homolog of the ATP7A gene (11-16). The discovery of the ATP7A gene led to vigorous studies on the function and metabolism of ATP7A and the intracellular copper transport system, as well as studies on the molecular genetics and clinical aspects of MNK.

2. MOLECULAR GENETICS 2.1. Background

The Menkes disease gene has been mapped to Xq13.3 and it is organized into 23 exons. It encodes a copper-transporting ATPase (ATP7A) consisting of 1500 amino acid residues, with a molecular mass of 165 kDa. The ATP7A gene is expressed in almost all tissues, except for the liver. The ATP7A protein contains six metal-binding domains near the N-terminus, a phosphorylation domain, a phosphatase domain, and eight transmembrane domains (Fig. 1). When the intracellular copper concentration is within the normal range, ATP7A is localized in the trans-Golgi network and it acts to

From: Handbook of Copper Pharmacology and Toxicology Edited by: E. J. Massaro © Humana Press Inc., Totowa, NJ

Fig. 1. Predicted structure of the Menkes copper-transporting ATPase (ATP7A). ■, six copper-binding domains; PD, phosphatase domain; CPC, cation channel; D, phosphorylation domain; ATP, ATP-binding domain.

transport copper from the cytosol into the Golgi apparatus and, subsequently, to exclude copper from the cells. When the intracellular copper concentration increases, ATP7A is transported to the plasma membrane (17,18).

2.2. Gene Defects

Patients with MNK exhibit a large variety of mutations in the ATP7A gene. Turner et al. summarized a total of 191 different mutations affecting the ATP7A gene, mainly in European and American patients with MNK and OHS (19). The mutations consisted of 7 chromosome mutations, 35 partial gene deletions, 39 deletion/insertion point mutations, 35 nonsense mutations, 43 splice-site mutations, and 32 missense mutations. These findings indicate that patients with MNK or OHS have no common mutations. The mutations in the ATP7A gene in 17 unrelated Japanese patients with classical MNK have been identified, and each patient was found to have a different mutation (Table 1). Splice-site mutations were found in two patients, and in both of these cases, only abnormal transcripts were found by reverse transcription-polymerase chain reaction (RT-PCR) analysis. All of the mutations identified in patients with MNK seem to have an important influence on the structure and function of ATP7A.

Mild MNK and OHS are very rare. To our knowledge, the mutations in patients with mild MNK and OHS have been reported in only 10 cases (Table 2) (10,11,20-25). One patient with mild MNK was found to have a missense mutation, and the mutant protein was located in the trans-Golgi network, but it failed to be transported to the plasma membrane in response to an increase intracellular copper concentration (20). Another patient with mild MNK was found to have a splice-site mutation resulting in the production of both normal and mutant transcripts. In patients with OHS reported by Kaler et al. and Qi et al., it seems that each of the mutations resulted in the production of a partially functional ATP7A protein. Seven of the mutations identified in patients with OHS are splice-site mutations. Five of these splice-site mutations have been reported to result in the production of the normal transcript as well as abnormal transcripts. A splice-site mutation in the ATP7A gene has also been identified in a Japanese patient with OHS (Table 2) (23). This mutation was found to be the same as one in a patient reported by M0ller et al. (22). However, the level of normal mRNA in M0ller et al's patient was 2-5% of that in unaffected individuals, whereas the level of normal mRNA in the Japanese patient was 19%. These differences suggest that the production of normal ATP7A mRNA

Table 1

ATP7A Mutations and Serum Levels of Copper and Ceruloplasmin in Japanese Patients with Menkes Disease

Cerulo-Serum Cu plasmin

Exon no. Nucleotide changesa Consequence (ßg/dL) (mg/dL)

Insertion/Deletion

Cerulo-Serum Cu plasmin

Exon no. Nucleotide changesa Consequence (ßg/dL) (mg/dL)

Insertion/Deletion

0 0

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