Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Menkes disease is an X-linked recessive disorder of the copper membrane transport system caused by mutations in the ATP7A gene. While various mutations in the ATP7A gene have been reported, a genotype-phenotype correlation has not been clearly defined. A novel mutation in the ATP7A gene in a Japanese patient with classical Menkes disease was identified via analysis of reverse-transcriptase polymerase chain reaction products and genomic DNA of the ATP7A gene. The nonsense mutation, L718X, was found to result in premature termination and immature ATP7A protein, unlikely to have normal functioning. Therefore, this nonsense mutation of the ATP7A gene is proposed to play a causative role in presenting the classical Menkes phenotype. Furthermore, four novel polymorphisms, C1535T (L464L), C2151T (T669I), G2253A (R703H), and C3677T (H1178Y) were also identified.
 ...
PMID:Novel mutation of L718X in the ATP7A gene in a Japanese patient with classical Menkes disease, and four novel polymorphisms in the Japanese population. 1104 17

Copper (Cu) is an essential trace element and constitutes the active center of the redox Cu enzymes such as Cu, Zn-superoxide dismutase (Cu, Zn-SOD), ceruloplasmin and cytochrome c oxidase. Among hereditary diseases due to a defect in the metabolism of Cu, Menkes disease (caused by a Cu deficiency) and Wilson disease (caused by the excessive accumulation of Cu) have been shown to be caused by the mutation of genes encoding Cu-binding ATPase for the efflux of Cu, ATP7A and ATP7B, respectively. Following the identification of these causative genes, intracellular Cu transporters (Cu chaperones) specific for the Golgi apparatus, mitochondria and Cu, Zn-SOD were discovered, and these findings have facilitated the study of the underlying mechanisms of the biological regulation of Cu. Apart from these physiological and biochemical studies, toxicological studies have elucidated the underlying mechanisms of the occurrence of acute hepatitis caused by the accumulation of Cu accumulating in the liver of an animal model for Wilson disease, LEC rats. In these toxicological studies, two biological aspects of metallothionein (MT), i.e., antioxidant and prooxidant depending on the Cu/Zn ratio in Cu-containing MT have been proposed. The present article overviews the recent findings on the biological regulation of Cu and on the toxicological aspect of Cu. It is known that Cu forms a stable ternary complex with molybdenum and sulfur under reductive conditions in the body. On the basis of this observation, tetrathiomolybdate (TTM) has been applied to remove Cu from the liver of Long-Evans rats with a cinnamon-like coat color (LEC) rats. Precise mechanisms underlying the complex formation between Cu bound to MT and TTM were presented, and an appropriate protocol for the chelation therapy was also proposed together with the mechanisms underlying the occurrence of side-effects.
 ...
PMID:[Biological regulation of copper and selective removal of copper: therapy for Wilson disease and its molecular mechanism]. 1108 2

Menkes disease is an X-linked recessive copper deficiency disorder caused by mutations in the ATP7A (MNK) gene. The MNK gene encodes a copper-transporting P-type ATPase, MNK, which is localized predominantly in the trans-Golgi network (TGN). The MNK protein relocates to the plasma membrane in cells exposed to elevated copper where it functions in copper efflux. A role for MNK at the TGN in mammalian cells has not been demonstrated. In this study, we investigated whether the MNK protein is required for the activity of tyrosinase, a copper-dependent enzyme involved in melanogenesis that is synthesized within the secretory pathway. We demonstrate that recombinant tyrosinase expressed in immortalized Menkes fibroblast cell lines was inactive, whereas in normal fibroblasts known to express MNK protein there was substantial tyrosinase activity. Co-expression of the Menkes protein and tyrosinase from plasmid constructs in Menkes fibroblasts led to the activation of tyrosinase and melanogenesis. This MNK-dependent activation of tyrosinase was impaired by the chelation of copper in the medium of cells and after mutation of the invariant phosphorylation site at aspartic acid residue 1044 of MNK. Collectively, these findings suggest that the MNK protein transports copper into the secretory pathway of mammalian cells to activate copper-dependent enzymes and reveal a second copper transport role for MNK in mammalian cells. These findings describe a single cell-based system that allows both the copper transport and trafficking functions of MNK to be studied. This study also contributes to our understanding of the molecular basis of pigmentation in mammalian cells.
 ...
PMID:The Menkes copper transporter is required for the activation of tyrosinase. 1109 60

Genomic DNA of 17 unrelated Japanese males with Menkes disease and 2 Japanese males with occipital horn syndrome were studied for mutations in the ATP7A gene. Using SSCP analysis and direct sequencing of the exons and the 5'-upstream region of the gene amplified by PCR, we identified 16 mutations in 16 of 17 males with Menkes disease, including 4 deletions, 2 insertions, 6 nonsense mutations, 2 missense mutations, and 2 splice-site mutations. All these mutations were those that affect the function of the gene. Of the two males with occipital horn syndrome, one had a splice-site mutation in intron 6 that led to normal-size and smaller-size transcripts. The amount of the normal-size transcripts in his cultured skin fibroblasts was 19% of the normal level. His serum copper and ceruloplasmin levels were normal, whereas his cultured skin fibroblasts contained increased levels of copper. These findings indicate that his mild clinical manifestations were due to the presence of normal-size and presumably functional transcripts of the gene. DNA sequencing analysis of the exons and 5'-upstream region of the ATP7A gene in 20 normal individuals and the 19 affected males identified 25 polymorphisms.
 ...
PMID:ATP7A gene mutations in 16 patients with Menkes disease and a patient with occipital horn syndrome. 1124 93

Menkes disease is an X-linked recessive disorder of the copper metabolism and affected males suffer a systemic copper deficiency due to malabsorption and defective distribution of dietary copper. It is caused by a defect in the Menkes (ATP7A) gene, which encodes a transmembrane copper-transporting P-type ATPase. A variety of mutations were reported; however, only a few mutations were reported in Asian patients. We identified four novel mutations and one known mutation in five Korean patients. Arg646Ter in exon 8, a novel mutation transmitted from his carrier mother, was identified in one patient. Prenatal DNA diagnosis on an unaffected fetus in this carrier mother was successfully accomplished. An additional three novel mutations, Leu706Arg in exon 9, Gly1118Asp in exon 17, and Gly1255Arg in exon 19, were identified. Splicing mutation was not identified. Menkes disease in Korean patients appears to be caused by heterogeneous mutations with different spectrums from Caucasian patients.
 ...
PMID:Identification of four novel mutations in classical Menkes disease and successful prenatal DNA diagnosis. 1135 Jan 87

The Enterococcus hirae CopB ATPase (EC 3.6.1.3) confers copper resistance to the organism by expelling excess copper. Two related human ATPase genes, ATP7A (EC 3.6.1.36) and ATP7B (EC 3.6.1.36), have been cloned as the loci of mutations causing Menkes and Wilson diseases, diseases of copper metabolism. Many mutations in these genes have been identified in patients. Since it has not yet been possible to purify the human copper ATPases, it has proved difficult to test the impact of mutations on ATPase function. Some mutations occur in highly conserved sequence motifs, suggesting that their effect on function can be tested with a homologous enzyme. Here, we used the E. hirae CopB ATPase to investigate the impact of such mutations on enzyme function in vivo and in vitro. The Menkes disease mutation of Cys-1000-->Arg, changing the conserved Cys-Pro-Cys ('CPC') motif, was mimicked in CopB. The corresponding Cys-396-->Ser CopB ATPase was unable to restore copper resistance in a CopB knock-out mutant in vivo. The purified mutant ATPase still formed an acylphosphate intermediate, but possessed no detectable ATP hydrolytic activity. The most frequent Wilson disease mutation, His-1069-->Gln, was introduced into CopB as His-480-->Gln (H480Q). This mutant CopB also failed to confer copper resistance to a CopB knock-out strain. Purified H480Q CopB formed an acylphosphate intermediate and retained a small, but significant, ATPase activity. Our results reveal that Cys-396 and His-480 of CopB are key residues for ATPase function, and similar roles are suggested for Cys-1000 and His-1069 of Menkes and Wilson ATPases respectively.
 ...
PMID:Structure-function analysis of purified Enterococcus hirae CopB copper ATPase: effect of Menkes/Wilson disease mutation homologues. 1141 52

We investigated the role of amidated neuropeptides, and specifically pituitary adenylyl cyclase-activating polypeptide (PACAP), in olfactory neurogenesis and olfactory receptor neuronal survival. Using both immunohistochemistry and in situ hybridization, we find that both peptidylglycine alpha-amidating monooxygenase (PAM), the enzyme responsible for amidation and therefore activation of all amidated neuropeptides, and amidated PACAP are expressed in developing and adult olfactory epithelium. Amidated PACAP is highly expressed in proliferative basal cells and in immature olfactory neurons. The PACAP-specific receptor PAC(1) receptor is also expressed in this population, establishing that these cells can be PACAP responsive. Experiments were conducted to determine whether amidated neuropeptides, such as PACAP38, might function in olfactory neurogenesis and neuronal survival. Addition of PACAP38 to olfactory cultures increased the number of neurons to >250% of control and stimulated neuronal proliferation and survival. In primary olfactory cultures, pharmacologically decreased PAM activity, as well as neutralization of PACAP38, caused neuron-specific loss that was reversed by PACAP38. Mottled (Brindled) mice, which lack a functional ATP7A copper transporter and serve as a model for Menkes disease, provided an in vivo partial loss-of-function PAM knock-out. These mice had decreased amidated PACAP production and concomitant decreased numbers of olfactory receptor neurons. These data establish amidated peptides and specifically PACAP as having important roles in proliferation in the olfactory system and suggest that a similar function exists in vivo.
 ...
PMID:Pituitary adenylyl cyclase-activating peptides and alpha-amidation in olfactory neurogenesis and neuronal survival in vitro. 1142 90

Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%-5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux.
 ...
PMID:A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease. 1143 6

Using the immunoblotting method, the synthesis of two copper-transporting P1-type ATPases, ATP7A (a candidate for the product of the Menkes disease gene) and ATP7B (presumed product of the Wilson disease gene), in the yolk sac cells of rat embryos at days 11 and 20 of embryogenesis was demonstrated. Concomitantly, yolk sac cells produce ceruloplasmin, a soluble copper-transporting glycoprotein, a proportion of which in secreted proteins progressively diminishes, attaining 5.2% at day 11 and 3.1% at day 20 of development. At different stages of embryogenesis, yolk sac cells synthesize two molecular forms of [14]C-ceruloplasmin, one of which is secreted towards the embryo, whereas the other, towards the decidual membrane. Two forms of ceruloplasmin secreted in polar directions differ in the rate of secretion. The role of the yolk sac as a key organ controlling the delivery and secretion of copper in the embryo during the postimplantation period is discussed.
 ...
PMID:[The role of the yolk sac in copper metabolism during rat embryogenesis]. 1154 10

Mutations of the ATP7A gene (OMIM 300011) lead to the Menkes disease (MD, OMIM 309400) involving impaired brain development, neurological degeneration, connective tissue abnormalities, and high lethality in early infancy. Occipital horn syndrome (OHS, OMIM 304150), a milder phenotype, is also caused by ATP7A gene mutations. In MD patients, an early copper-histidine treatment may prevent the neurological impairment and prolong survival leading to an OHS phenotype. To demonstrate the genotype/phenotype correlation, two male patients are reported with different ATP7A gene mutations and several phenotypes. In the first patient with the MD phenotype, a mutation within the exon 20 (Gln1288Ter) was found producing a stop codon just prior to the highly conserved ATP binding domain. The OHS phenotype of the second patient was caused by a splice site mutation involving the position +6 of intron 6 within a copper binding domain. Small amounts of correctly spliced ATP7A transcript were sufficient to develop the milder OHS phenotype in this patient (OMIM 30001.0006). In conclusion, mutations of the copper transporting P-type ATPase ATP7A gene cause distinct human diseases showing some genotype/phenotype correlation and implications for treatment.
 ...
PMID:Disturbed copper transport in humans. Part 1: mutations of the ATP7A gene lead to Menkes disease and occipital horn syndrome. 1193 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>