Molecular Genetics of M enkes Disease

Abstract

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.