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J Med Genet 44:673-688 doi:10.1136/jmg.2007.052746
  • Review

Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes

  1. P de Bie1,2,
  2. P Muller1,2,
  3. C Wijmenga2,3,
  4. L W J Klomp1
  1. 1
    Laboratory of Metabolic and Endocrine Diseases, University Medical Center, Utrecht, The Netherlands
  2. 2
    Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
  3. 3
    Department of Genetics, University Medical Center, Groningen, The Netherlands
  1. L W J Klomp, Laboratory of Metabolic and Endocrine Diseases, Room KC.02.069.1, Lundlaan 6, 3584 EA Utrecht, The Netherlands; l.klomp{at}umcutrecht.nl
  • Received 2 July 2007
  • Revised 14 August 2007
  • Accepted 15 August 2007
  • Published Online First 23 August 2007

Abstract

The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein–protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.

Footnotes

  • Competing interests: None declared.

  • Abbreviations:
    A-domain
    actuator domain
    AIPP1
    ATPase interacting PDZ protein 1
    CCS
    copper chaperone for superoxide dismutase 1
    CT
    copper toxicosis in Bedlington terriers
    CTR1
    copper transporter 1
    ER
    endoplasmic reticulum
    ETIC
    endemic Tyrolean infantile cirrhosis
    ICC
    Indian childhood cirrhosis
    ICT
    idiopathic copper toxicosis
    LEC
    Long–Evans cinnamon
    MBS
    metal-binding site
    MD
    Menkes disease
    N-domain
    nucleotide-binding domain
    NF
    nuclear factor
    OHS
    occipital horn syndrome
    OMIM
    Online Mendelian Inheritance in Man
    P-domain
    phosphorylation domain
    PLZF
    promyelocytic leukemia zinc finger protein
    SOD1
    superoxide dismutase 1
    TGN
    trans-Golgi network
    WD
    Wilson disease