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

The gene responsible for Menkes syndrome has been assigned to Xq13 by a combination of comparative mapping and linkage analysis. A previous report has mapped the translocation breakpoint associated with the disease in a female patient to an interval delimited by PGK1 and a group of six more proximal Xq13 markers, including DXS56. We have characterized a number of PGK1- or DXS56-positive YACs, from which we have generated six new markers. One of them identifies a small overlap region between a PGK1-positive YAC and three DXS56-positive YACs, distal to the Menkes breakpoint. A 560-kb region covered by a DXS56-positive YAC has been restriction-mapped and subcloned, disclosing a 187-kb MluI fragment astride the breakpoint. A probe mapping distal to the rearrangement in the same interval reveals altered PGFE fragments in a hybrid constructed from the translocation patient's DNA. We describe the development of a cosmid contig extending 150 kb from a nearby CpG island across the breakpoint. This contig includes four adjacent clones displaying cross-specific hybridization.
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PMID:Fine mapping and cloning of the breakpoint associated with Menkes syndrome in a female patient. 142 84

The proximal long arm of the human X chromosome (Xcen----Xq13) encompasses an estimated 23 megabases of DNA and contains numerous identified genetic loci. In order to generate a highly enriched source of DNA from this region, radiation-reduced human-hamster hybrids were constructed and screened to identify those that contained at least part of proximal Xq. Eight such hybrids were identified and characterized by Southern blot and fluorescence in situ hybridization analyses to determine more precisely the human DNA complement in each. One hybrid contains the entire proximal long arm and will be useful for mapping Xcen----Xq13 in its entirety and for localizing genes within this region. Another hybrid contains a smaller portion of the proximal long arm that includes the region reported to contain the gene for Menkes' disease.
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PMID:Isolation and characterization of radiation-reduced hybrids containing portions of the proximal long arm of the human X chromosome: identification of hybrids containing the Menkes' disease locus. 149 17

Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses were tested using 11 polymorphic DNA markers. From two-point linkage analyses high lod scores are seen for DXS146 (pTAK-8; maximal lod score 3.16 at recombination fraction [theta] = .0), for DXS1 (p-8; maximal lod score 3.44 at theta = .0), for PGK1 (maximal lod score 2.48 at theta = .0), and for DXS3 (p19-2; maximal lod score 2.90 at theta = .0). This indicates linkage to the pericentromeric region. Multilocus linkage analyses of the same data revealed a peak for the location score between DXS146(pTAK-8) and DXYS1X(pDP34). The most likely location is between DXS159 (cpX289) and DXYS1X(pDP34). Odds for this location relative to the second-best-supported region, between DXS146(pTAK-8) and DXS159 (cpX289), are better than 74:1. Visualization of individual recombinant X chromosomes in two of the Menkes families showed the Menkes locus to be situated between DXS159(cpX289) and DXS94(pXG-12). Combination of the present results with the reported absence of Menkes symptoms in male patients with deletions in Xq21 leads to the conclusion that the Menkes locus is proximal to DXSY1X(pDP34) and located in the region Xq12 to Xq13.3.
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PMID:Multipoint linkage analysis in Menkes disease. 157 Aug 30

Cytochrome c oxidase (COX) is a complex enzyme composed of 13 subunits, three of which are encoded by the mitochondrial DNA (mtDNA). The other 10 subunits are encoded by the nuclear DNA, synthesized in the cytoplasm, and transported into the mitochondria. The complexity of the enzyme and its dual genetic control explain the heterogeneity of clinical phenotypes associated with COX deficiency. There are two major syndromes, one characterized by muscle involvement (fatal infantile or benign infantile myopathy), the other dominated by brain disease (Leigh syndrome, myoclonic epilepsy with ragged red fibers, Menkes' disease). Partial defects of COX have been shown in muscle of patients with progressive external ophthalmoplegia, either alone (ocular myopathy) or as part of Kearns-Sayre syndrome. Biochemical studies have documented either muscle-specific or generalized defects of COX; COX deficiency is reversible in the benign infantile myopathy. Immunologically detectable protein may be normal (benign myopathy) or variably decreased (fatal myopathy, Leigh syndrome). The subunit pattern of COX is normal by immunoblot in patients with fatal myopathy and Leigh syndrome; a disproportionate decrease of subunit II was seen in a patient with myoclonic epilepsy with ragged red fibers. Availability of the three mtDNA genes and of complementary DNA probes for eight of the 10 nuclear DNA-encoded subunits makes it possible to investigate the different diseases at the molecular level. Large deletions of mtDNA have been found in patients with ocular myopathy and Kearns-Sayre syndrome: the deleted mtDNA appear to be transcribed but not translated, thus explaining the partial COX deficiency.
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PMID:Cytochrome c oxidase deficiency. 217 26

The wet weights, contents of DNA, RNA and protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) activities were examined in the cerebrum, brain stem and cerebellum from macular mutant mouse, as a model animal for Menkes' kinky hair disease (MKHD). The DNA, RNA and protein contents in the cerebellum from macular hemizygous males (Ml/y) were affected to a much greater extent than those in the cerebrum and the brain stem. This suggests that the main affected part of the brain in Ml/y mouse is the cerebellum. CNP activities in the Ml/y mouse showed a significant decrease in every part of the brain after day 10. This finding may coincide with the changes in myelination in human MKHD.
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PMID:Biochemical study on the brain of the macular mutant mouse as a model of Menkes' kinky hair disease. 245 26

Both deficiency and excess of copper induce toxic effects on mammalian cell systems in vivo and in vitro. The effects can be related to the affinities of Cu(II) ions for specific cell components. The nucleus is a potential site for temporary Cu storage while primary targets for free Cu(II) ions are the thiol groups which reduce the ions to Cu(I). Cu(II) ions show a high affinity for nucleic acids, binding with DNA both at intrastrand and interstrand levels, possibly through intercalation between GC pairs. The ability to chelate Cu(II) ions is seen to be of the order: purine greater than purine ribonucleotides greater than purine ribonucleoside greater than pyrimidine ribonucleotides. Copper is an integral part of enzyme activation and enters into the molecular structure of several proteins, like ceruloplasmin. Cu(II) ion is a potential mutagenic agent as seen by its property of inducing infidelity in DNA synthesis in vitro. Teratogenic activities of copper have been reported but carcinogenicity is not yet confirmed. Copper is an essential component of chromatin and is known to accumulate preferentially in the heterochromatic regions. External application of higher doses, however, induces both clastogenic effects and spindle disturbances. In certain forms, inorganic copper enhances the clastogenic activity of other agents. The most widely studied human genetic maladies linked with copper metabolism are Menkes' and Wilson's diseases. Several mutations are known which influence Cu homeostasis in mammals. Such mutations in mice have been used extensively for biochemical studies.
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PMID:Effects of copper on mammalian cell components. 246 42

Increased 64Cu uptake into cultured cells is a biochemical marker for mutant cells in Menkes' disease (McKusick 30940). Using this marker selective prenatal diagnosis has been carried out in more than 80 at-risk pregnancies. The 64Cu uptake into cultures from affected male fetuses is however, negatively correlated to the fetal age at amniocentesis. After the 18th week of gestation the risk of false negatives is significant. Using copper uptake into uncloned cultures, a number of obligate and possible carriers showed significantly increased values, but the range of values of obligate carriers considerably overlapped those of the normal controls. All values of normal controls were within a limited range and values above the upper limit in females at risk must, therefore, be caused by mutant cells and establish the carrier diagnosis. However, the extreme skewing of the distribution towards normal values in obligate carriers indicates a strong selection against the mutant cell type and this will hamper the detection of all female carriers in risk families. C-banding heteromorphism of the X-chromosome provides a supplementary carrier detection method. Linkage analysis in five Danish families demonstrated a close physical relationship between the gene for Menkes' disease and the centromere region. By comparative gene mapping (mouse/man) the most likely localization of the gene for Menkes' disease can be suggested to be in band q13 on the long arm of the human X-chromosome. This regional assignment facilitates the choice of appropriate X-specific DNA probes in search for linkage at the DNA level.
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PMID:Menkes' X-linked disease: prenatal diagnosis and carrier detection. 641 76

In a large kindred with X-linked Menkes disease, linkage studies were performed with a restriction fragment length polymorphism (RFLP) that had been found with a cloned hybridisation probe from the proximal short arm of the X chromosome. This RFLP was considered as a potential genetic marker since the Menkes gene seems to be located near the centromere. Moreover, there is circumstantial evidence that in the (para) centric region of the X chromosome cross-overs are relatively rare. Unexpectedly, however, at least two cross-overs were detected in this family which suggests that the DNA sequence employed is of limited use for early diagnosis and carrier detection in this fatal hereditary disorder.
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PMID:Menkes kinky hair disease: a search for closely linked restriction fragment length polymorphism. 657 80

We have assigned the structural gene (Mt-1) coding for the murine metal-binding protein metallothionein I (MT-1) to mouse chromosome 8 by using a cloned DNA probe for mouse Mt-1 in combination with a panel of Chinese hamster-mouse somatic cell hybrid clones segregating mouse chromosomes. Analysis of hybrid cell extracts for the presence of mouse Mt-1 or MT-1 mRNA revealed concordant segregation of Mt-1 with mouse glutathione reductase, an enzyme marker for mouse chromosome 8, but discordant segregation with enzyme markers for 14 other mouse chromosomes. Karyotype analyses of seven informative hybrid clones confirmed the assignment of mouse Mt-1 to chromosome 8. Menkes' disease in man and the mottled mutation (Mo) in the mouse, which provides an animal model of Menkes' disease, are both X-linked degenerative neurologic disorders involving abnormal copper metabolism and increased levels of intracellular metallothionein protein. Fibroblasts from Mo male mice have increased amounts of MT-1 mRNA, suggesting that both Mo and Menkes' disease may be due to a metallothionein gene mutation. However, our assignment of Mt-1 to mouse chromosome 8, rather than the X chromosome, demonstrates that a mutation in mouse Mt-1 or a closely linked regulatory gene is not the primary defect in Mo, and implies that a metallothionein gene mutation is not the genetic defect in human Menkes' disease.
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PMID:The metallothionein-I gene maps to mouse chromosome 8: implications for human Menkes' disease. 668 8

Human metallothioneins are encoded by a complex multigene family. The chromosomal location of these genes has been determined by gel transfer hybridization analysis of the DNA from human-rodent cell hybrids. Chromosome 16 contains a cluster of metallothionein sequences, including two functional metallothionein I genes and a functional metallothionein II gene. The remaining sequences, including a processed pseudogene, are dispersed to at least four other autosomes. The absence of metallothionein sequences from the X chromosome indicates that Menkes' disease, an X-linked disorder of copper metabolism, affects metallothionein expression by a trans-acting mechanism.
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PMID:Chromosomal location of human metallothionein genes: implications for Menkes' disease. 671 35


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