Molecular Genetics of Menkes Disease

Abstract

Menkes disease is a recessive childhood disorder that results from systemic copper deficiency. This deficiency leads to loss of cuproenzyme function and subsequent defects in the hair, skin and vasculature. Patients also display severe neurodegeneration linked to copper deficiency in the brain. Menkes disease is monogenic and caused by loss‐of‐function mutations in the copper transporter ATP7A. ATP7A is responsible for the provision of copper to secretory cuproenzymes and for exporting excess copper out of the cell. Mutations in ATP7A associated with Menkes disease are heterogenous in both type and primary structure location, and no specific mutations are observed more frequently than others. Allelic variants that do not lead to complete loss of ATP7A function produce occipital horn syndrome and a form of spinal muscular atrophy.

Key Concepts

  • Menkes disease is an X‐linked recessive disorder with an occurrence of 1/40 000–1/360 000.
  • Menkes disease presents 2–12 months after birth as hair, skin and joint abnormalities and later progresses to severe neurodegeneration.
  • Loss‐of‐function mutations in the copper transporter ATP7A produce Menkes disease, and milder mutations produce occipital horn syndrome, characterised predominantly by connective tissue abnormalities, and a variant of spinal muscular atrophy.
  • ATP7A is a Golgi‐localised protein that provides copper to secretory cuproenzymes. Under conditions of excess intracellular copper, ATP7A localises to the plasma membrane where it pumps excess copper out of the cell.
  • Over 350 mutations have been identified in ATP7A that lead to Menkes disease. These mutations do not cluster to particular sequences in the gene and include a range of mutation types such as missense mutations, deletions and nonsense mutations, among others.
  • Loss of ATP7A‐dependent cuproenzyme function accounts for many of the phenotypes associated with Menkes disease. For example, lack of copper incorporation into the melanin‐producing enzyme tyrosinase leads to hypopigmentation in patients.
  • The pathogenesis of the severe neurodegeneration observed in Menkes patients is not well understood and is an active area of investigation.

Keywords: ATP7A; copper; neurodegeneration; neurodevelopmental disorder; Parkinson; golgi; Menkes disease

Figure 1. Menkes disease phenotypes. (a) Brain MRI of an 8‐month‐old Menkes patient displaying atrophy of the brain matter coinciding with enlarged cerebrospinal fluid cavity. (b) Light microscopy reveals characteristic twisted hair or pilli torti. (c) An infant with Menkes disease displaying hypopigmentation of the hair and skin as well as sparse, coarse hair. Images from Datta et al. 2008. PMID 18801184 under Wikimedia Commons.
Figure 2. ATP7A expression pattern. Expression profile of ATP7A in males and females according to FANTOM (Functional Annotation of the Mammalian Genome). Data were analysed and depicted using the Expression Atlas Engine (https://www.ebi.ac.uk/gxa/home). Light blue depicts low expression and dark blue/purple high expression levels.
Figure 3. ATP7A protein architecture. ATP7A is a transmembrane protein with several conserved domains. There are eight copper binding sites with the sequence MXCXSC at the N‐terminus. Two of the transmembrane domains contain functional sequences: one is required for trans‐Golgi network retention, and the other contains sequences that allow copper to pass from the cytosol to the lumen of the Golgi. ATP7A contains three conserved, cytosolic domains required for ATPase activity: the A‐domain contains phosphatase activity, the P‐domain is phosphorylated during catalysis and the N‐domain contains ATP‐binding activity. There are two other functional domains at the C‐terminus, a dileucine motif required for endocytosis and a PDZ domain required for appropriate plasma membrane localisation in some polarised cell types.
Figure 4. Copper binding proteins in the cell. Copper enters the cell via the copper transporter CTR1 (red circle). CTR1 then transfers copper to three cytosolic copper chaperones, ATOX1, CCS and COX17, which deliver the metal to the appropriate compartment. Of the copper chaperones, ATOX1 provides copper to the Golgi‐resident transporters, ATP7A and ATP7B (blue circles). These P‐type ATPases pump the copper into the lumen of the Golgi, where it is bound by secretory apoenzymes that require copper as a cofactor (orange circle and arrow). Under steady‐state conditions, ATP7A and B are localised to the Golgi complex but translocate to the plasma membrane to pump copper out of the cell if the intracellular copper levels become elevated. CCS, the aptly named copper chaperone for SOD1, provides copper to the cytosolic superoxide dismutase 1 (purple circle). Finally, COX17 is thought to be responsible for copper provision to the mitochondria, where the metal is required as a cofactor for cytochrome c oxidase (green circle). In addition to these copper‐specific transporters and chaperones, metallothioneins (yellow circles labelled MT) and glutathione (GSH) possess general metal‐binding properties, and their expression is modified as necessary to buffer excess copper.
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Further Reading

Kaler SG (2011) ATP7A‐related copper transport diseases‐emerging concepts and future trends. Nature Reviews. Neurology 7 (1): 15–29.

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Comstra, Heather S, and Faundez, Victor(Jul 2017) Molecular Genetics of Menkes Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027315]