ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Abstract

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.

Copper-histidine therapy in an infant with novel splice-site variant in theATP7Agene of Menkes disease: the first experience in South East Asia and literature review

“…The immature blood-brain barrier (BBB) in infant, which allows copper transport across astrocytes to neuron cells, plays a critical role for therapy 33 35. Additionally, ATP7A is highly expressed in neonatal brain, which controls the copper transport across the BBB,7 indicating an age-dependent period of increased copper influx. Thus, the more mature BBB, the greater reduction of copper across the brain.…”

“…The mutations cause copper trafficking in cells and a decrease in cuproenzyme activity. The systemic manifestations include hypopigmentation, growth and mental retardation, cerebral and cerebellar degeneration, connective tissue abnormalities and almost all patients die before the age of 3 years 5–7. Clinical presentation of this disease ranges from occipital horn syndrome (MIM# 304150), in its mildest form, to severe classic form (90%–95% of case) 8.…”

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

“…These three entities are best described as a clinical continuum spectrum from severe to mild forms. MNK is characterized by epilepsy, progressive neurodegeneration, conjunctive tissue abnormalities, a distinctive hair appearance and short lifespan (age of death < 3 years) [ 131 ]. A case of an unusual phenotype resembling WD was reported by Bansagi et al [ 132 ].…”

Pili Torti: A Feature of Numerous Congenital and Acquired Conditions

“…Menkes disease, also known as kinky hair disease, is a rare neurodegenerative disease with X-linked recessive inheritance [45]. It is caused by different mutations in the ATPase Copper Transporting Alpha (ATP7A) gene, that result in the failure of copper absorption in the intestines followed by copper deficiency [46].…”