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FB2026_01
,
released March 12, 2026
This report describes Menkes disease (MNK); MNK exhibits sex-linked recessive inheritance. The human gene implicated in this disease is ATP7A, which encodes Cu(2+)-transporting ATPase, alpha polypeptide, a transmembrane copper-transporting P-type ATPase. There is one high-scoring ortholog in Drosophila, ATP7, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. ATP7A is associated with several other diseases, neuronopathy, distal hereditary motor, X-linked (MIM:300489, FBhh0000077) and occipital horn syndrome (MIM:304150, FBhh0000078). Dmel\ATP7 is also orthologous to a paralogous gene in human, ATP7B.
Multiple UAS constructs of the human Hsap\ATP7A gene have been introduced into flies, including wild-type and a variant implicated in disease (see FBhh0000438). ATP7B has not been introduced into flies.
A variant analogous to one specifically implicated in Menkes disease has been characterized in flies and been shown to act like a null mutation. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G1036E in the fly ATP7 gene (corresponds to G1300E in the human ATP7A gene). See the 'Disease-Implicated Variants' table below.
See the human disease model report for copper metabolism disorders, ATP7-related (FBhh0000438) for additional information on experimental results using Drosophila models of this and related diseases.
[updated Feb. 2024 by FlyBase; FBrf0222196]
[MENKES DISEASE; MNK](https://omim.org/entry/309400)
[ATPase, Cu(2+)-TRANSPORTING, ALPHA POLYPEPTIDE; ATP7A](https://omim.org/entry/300011)
Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes (reviewed in De Bie, et al, 2007, pubmed:17717039).
Menkes disease is a disorder of copper transport caused by mutations in the copper-transporting ATPase gene (ATP7A). Infants with classic Menkes disease appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Temperature instability and hypoglycemia may be present in the neonatal period. Death usually occurs by age three years. [from GeneReviews, ATP7A-Related Copper Transport Disorders, pubmed:20301586 2015.12.18]
Menkes disease is caused by recessive mutation in ATP7A. [From MIM:309400, 2015.12.18]
Similar abnormalities of copper and collagen metabolism were found in the cultured fibroblasts of 13 patients with Menkes syndrome and 2 patients with E-D IX. In both disorders, fibroblasts had markedly increased copper content and rate of incorporation of (64)Cu, and accumulation was in metallothionein (see MIM:156350) or a metallothionein-like protein as previously established for Menkes cells. Histochemical staining showed that copper was distributed uniformly throughout the cytoplasm in both cell types, this location being consistent with accumulation in metallothionein. Both fibroblast types showed very low lysyl oxidase activity and increased extractability of newly synthesized collagen, but no abnormality in cell viability, duplication rate, prolyl 4-hydroxylase activity, or collagen synthesis rate. Skin biopsy specimens from one E-D IX (MIM:304150) patient showed the same abnormalities in lysyl oxidase activity and collagen extractability. Fibroblasts of the mother of E-D IX patients showed increased (64)Cu incorporation. The similarities in biochemical findings between type IX Ehlers-Danlos syndrome and Menkes syndrome may indicate allelism (Peltonen, et al., 1983, pubmed:6140952). In studies of cultured cells from both conditions, it could not be demonstrated that there was secreted into the medium or contained in the cell any significant amounts of copper-deficient, catalytically inactive lysyl oxidase protein. Although the rapid degradation of a mutant protein could not be excluded, the authors favored the idea that synthesis of the lysyl oxidase protein is impaired (Kuivaniemi et al., 1985 pubmed:9556668). [From MIM:309400, 2015.12.18]
The ATP7A gene encodes a transmembrane copper-transporting P-type ATPase, Cu(2+)-transporting ATPase, alpha polypeptide. P-type ATPases are a family of integral membrane proteins that use an aspartylphosphate intermediate to transport cations across membranes. The 1,500-residue ATP7A protein was found to have the characteristics of a copper-binding protein. It has 6 N-terminal copper binding sites and a catalytic transduction core with several functional domains (Vulpe et al., 1993, pubmed:8490659). [From MIM:300011 and MIM:304150, 2015.12.18]
Many to one: 2 human to 1 Drosophila.
Ortholog of human ATP7A and ATP7B (1 Drosophila to 2 human).
Dmel\ATP7 shares 46% identity and 62% similarity with human ATP7A, and with 47% identity and 62% similarity human ATP7B.