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)

Ultrastructural studies of the skin and aorta of a patient with Menkes disease, an X-linked recessive disorder of copper metabolism, are described. Dermal thickness was normal, while dermal collagen fibrils exhibited a heterogeneous size range, with a mean diameter smaller than normal. Long-spacing collagen was often observed near fibroblasts, the plasma membranes of which were decorated by aggregates of interwoven filaments. Dermal elastin fibers were scarce and consisted of thin strands of amorphous elastin associated with numerous microfibrils. In the aorta, the amount of collagen was normal, although the fibrils displayed a broader range of diameters than normal, with a slightly smaller mean. Elastin fibers showed considerable disruption, appearing fragmented and wider than normal, and displaying irregular contours. The inclusion of cationic dyes during tissue fixation gave rise to numerous electron-dense precipitates within the elastin fibers, suggesting the presence there of glycosaminoglycans or proteoglycans, among which unsulfated and sulfated chondroitins were demonstrated by immunoelectron microscopy to be prominent. Heparan sulfate, observed to be a constituent of normal elastin fibers, was much reduced in amount. Elastin was also found associated with glycosaminoglycans in the soluble matrix of the aortic wall.
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PMID:Ultrastructural analysis of skin and aorta from a patient with Menkes disease. 799 78

The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy.
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PMID:The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. 2674 66