Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A

Hum Mutat. 2005 Aug;26(2):84-93. doi: 10.1002/humu.20190.


ATP7A encodes a copper-translocating ATPase that belongs to the large family of P-type ATPases. Eight conserved regions define the core of the P-type ATPase superfamily. We report here the identification of 21 novel missense mutations in the conserved part of ATP7A that encodes the residues p.V842-p.S1404. Using the coordinates of X-ray crystal structures of the sarcoplasmic reticulum Ca(2+)-ATPase, as determined in the presence and absence of Ca(2+), we created structural homology models of ATP7A. By mapping the substituted residues onto the models, we found that these residues are more clustered three-dimensionally than expected from the primary sequence. The location of the substituted residues in conserved regions supports the functional similarities between the two types of P-type ATPases. An immunofluorescence analysis of Menkes fibroblasts suggested that the localization of a large number of the mutated ATP7A protein variants was correct. In the absence of copper, they were located in perinuclear regions of the cells, just like the wild type. However, two of the mutated ATP7A variants showed only partly correct localization, and in five cultures no ATP7A protein could be detected. These findings suggest that although a disease-causing mutation may indicate a functional significance of the affected residue, this is not always the case.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics*
  • Amino Acid Sequence
  • Calcium-Transporting ATPases / chemistry
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / genetics*
  • Chromosome Mapping
  • Conserved Sequence
  • Copper-Transporting ATPases
  • Crystallography, X-Ray
  • Fibroblasts / metabolism
  • Humans
  • Menkes Kinky Hair Syndrome / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sequence Homology, Amino Acid


  • Cation Transport Proteins
  • Adenosine Triphosphatases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
  • ATP7A protein, human
  • Copper-Transporting ATPases

Associated data

  • OMIM/277900
  • OMIM/300011
  • OMIM/309400