Dataset Information

Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.

ABSTRACT: The connective-tissue disorder occipital horn syndrome (OHS) is hypothesized to be allelic to Menkes disease. The two diseases have different clinical presentations but have a similar abnormality of copper transport. Mice hemizygous for the blotchy allele of the X-linked mottled locus have similar connective-tissue defects as OHS and may represent a mouse model of this disease. We have analyzed the Menkes/mottled copper-transporting ATPase in these two potentially homologous disorders and have identified similar splicing mutations in both. Some expression of normal mRNA was detectable by reverse transcription-PCR in the mutant tissues. These findings contrast with the more debilitating mutations observed in Menkes disease and suggest that low amounts of an otherwise normal protein product could result in the relatively mild phenotype of OHS and of the blotchy mouse.

SUBMITTER: Das S

PROVIDER: S-EPMC1801180 | biostudies-other | 1995 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.

Das S S Levinson B B Vulpe C C Whitney S S Gitschier J J Packman S S

American journal of human genetics 19950301 3

The connective-tissue disorder occipital horn syndrome (OHS) is hypothesized to be allelic to Menkes disease. The two diseases have different clinical presentations but have a similar abnormality of copper transport. Mice hemizygous for the blotchy allele of the X-linked mottled locus have similar connective-tissue defects as OHS and may represent a mouse model of this disease. We have analyzed the Menkes/mottled copper-transporting ATPase in these two potentially homologous disorders and have i ...[more]

PMID: 7887410

Similar Datasets

Project description:OBJECTIVE:Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, we show that Cu chelator markedly inhibited Ang II (angiotensin II)-induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II-induced AAA formation. Conversely, Cu transport dysfunctional ATP7Amut/+/ApoE-/- mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1-/-/ApoE-/- mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7Amut/+/ApoE-/- mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-?B negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7Amut/+/ApoE-/- mice and reversed by locked nucleic acid-anti-miR-125b infusion. CONCLUSIONS:ATP7A downregulation/dysfunction promotes AAA formation via upregulating miR-125b, which augments proinflammatory signaling in a Cu-dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.

Dataset Information

Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.

Publications

Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets