Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions

Hum Mol Genet. 1994 Sep;3(9):1647-56. doi: 10.1093/hmg/3.9.1647.


Wilson disease is an autosomal recessive disorder of copper transport. Disease symptoms develop from the toxic build-up of copper primarily in the liver, and subsequently in the brain, kidney, cornea and other tissues. A candidate gene for WD (ATP7B) has recently been identified based upon apparent disease-specific mutations and a striking amino acid homology to the gene (ATP7A) responsible for another human copper transport disorder, X-linked Menkes disease (MNK). The cloning of WD and MNK genes provides the first opportunity to study copper homeostasis in humans. A preliminary analysis of the WD gene is presented which includes: isolation and characterization of the 5'-end of the gene; construction of a genomic restriction map; identification of all 21 exon/intron boundaries; characterization of extensive alternative splicing in brain; prediction of structure/function features of the WD and MNK proteins which are unique to the subset of heavy metal-transporting P-type ATPases; and comparative analysis of the six metal-binding domains. The analysis indicates that WD and MNK proteins belong to a subset of transporting ATPases with several unique features presumably reflecting their specific regulation and function. It appears that the mechanism of alternative splicing serves to regulate the amount of functional WD protein produced in brain, kidney, placenta, and possibly in liver.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Alternative Splicing
  • Amino Acid Sequence
  • Base Sequence
  • Binding Sites / genetics
  • Biological Evolution
  • Brain / enzymology
  • Cation Transport Proteins*
  • Chromosome Mapping
  • Cloning, Molecular
  • Copper / metabolism
  • Copper-Transporting ATPases
  • DNA, Complementary / genetics
  • Female
  • Hepatolenticular Degeneration / enzymology
  • Hepatolenticular Degeneration / genetics*
  • Humans
  • Ion Transport
  • Kidney / enzymology
  • Liver / enzymology
  • Molecular Sequence Data
  • Placenta / enzymology
  • Pregnancy
  • Structure-Activity Relationship
  • Tissue Distribution


  • Cation Transport Proteins
  • DNA, Complementary
  • Copper
  • Adenosine Triphosphatases
  • ATP7B protein, human
  • Copper-Transporting ATPases

Associated data

  • GENBANK/U11700