A comparison of the mutation spectra of Menkes disease and Wilson disease

• Published in: Human genetics 2004, Vol.114 (2), p.165-172
• Main Authors: HSI, Gloria, COX, Diane W
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino acids; Analysis; Biological and medical sciences; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Classical genetics, quantitative genetics, hybrids; Copper - metabolism; Copper-transporting ATPases; Databases, Factual; Fundamental and applied biological sciences. Psychology; Gene mutations; Genes; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Hepatolenticular Degeneration - genetics; Hepatolenticular Degeneration - metabolism; Human; Humans; Medical sciences; Menkes Kinky Hair Syndrome - genetics; Menkes Kinky Hair Syndrome - metabolism; Metabolic diseases; Metals (hemochromatosis...); Mutation - genetics; Other metabolic disorders; Proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sequence Alignment
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-003-1045-y

The genes for two copper-transporting ATPases, ATP7A and ATP7B, are defective in the heritable disorders of copper imbalance, Menkes disease (MNK) and Wilson disease (WND), respectively. A comparison of the two proteins shows extensive conservation in the signature domains, with amino acid identities outside of the conserved domains being limited. The mutation spectra of MNK and WND were compared to confirm and refine further regions critical for normal function. Mutations were found to be relatively widespread; however, the majority was concentrated within defined functional domains and membrane-spanning segments, reinforcing the importance of these regions for protein function. Of the total published point mutations in ATP7A, 23.0% are splice-site, 20.7% nonsense, 17.2% missense, and 39.1% small insertions/deletions. There is a high prevalence (58.2%) of missense mutations in ATP7B. For the other mutations in ATP7B, 7.4% are splice-site, 7.4% nonsense, and 27.0% small insertions/deletions. A region of possible importance is the intervening sequence between the last copper-binding domain and the first transmembrane helix, as this region has a high percentage of MNK mutations. Similarly, the region containing the ATP-binding domain has 24.6% of all WND mutations. The study of mutation locations is useful for defining critical regions or residues and for efficient molecular diagnosis.