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A New Zebrafish Model for Pseudoxanthoma Elasticum.

ABSTRACT: Calcification of various tissues is a significant health issue associated with aging, cancer and autoimmune diseases. There are both environmental and genetic factors behind this phenomenon and understanding them is essential for the development of efficient therapeutic approaches. Pseudoxanthoma elasticum (PXE) is a rare genetic disease, a prototype for calcification disorders, resulting from the dysfunction of ABCC6, a transport protein found in the membranes of cells. It is identified by excess calcification in a variety of tissues (e.g., eyes, skin, arteries) and currently it has no cure, known treatments target the symptoms only. Preclinical studies of PXE have been successful in mice, proving the usefulness of animal models for the study of the disease. Here, we present a new zebrafish (Danio rerio) model for PXE. By resolving some ambiguous assemblies in the zebrafish genome, we show that there are two functional and one non-functional paralogs for ABCC6 in zebrafish (abcc6a, abcc6b.1, and abcc6b.2, respectively). We created single and double mutants for the functional paralogs and characterized their calcification defects with a combination of techniques. Zebrafish deficient in abcc6a show defects in their vertebral calcification and also display ectopic calcification foci in their soft tissues. Our results also suggest that the impairment of abcc6b.1 does not affect this biological process.

SUBMITTER: Czimer D

PROVIDER: S-EPMC7985086 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A New Zebrafish Model for Pseudoxanthoma Elasticum.

Czimer Dávid D Porok Klaudia K Csete Dániel D Gyüre Zsolt Z Lavró Viktória V Fülöp Krisztina K Chen Zelin Z Gyergyák Hella H Tusnády Gábor E GE Burgess Shawn M SM Mócsai Attila A Váradi András A Varga Máté M

Frontiers in cell and developmental biology 20210309

Calcification of various tissues is a significant health issue associated with aging, cancer and autoimmune diseases. There are both environmental and genetic factors behind this phenomenon and understanding them is essential for the development of efficient therapeutic approaches. Pseudoxanthoma elasticum (PXE) is a rare genetic disease, a prototype for calcification disorders, resulting from the dysfunction of ABCC6, a transport protein found in the membranes of cells. It is identified by exce ...[more]

PMID: 33768091

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Project description:Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Project description:ImportanceAcute retinopathy may partly explain variable disease manifestation and vision loss in patients with pseudoxanthoma elasticum (PXE). The diagnosis of this likely autoimmune process may inform patient counseling and treatment approaches.ObjectiveTo characterize acute retinopathy in patients with PXE as a disease manifestation that may be associated with profound visual impairment.Design, setting, and participantsThis single-center case series was conducted from May 2013 to October 2018. It used the patient database of the Department of Ophthalmology at the University of Bonn, a referral center for PXE in Germany. Patients at this center with genetically confirmed PXE and who met the inclusion criteria were included (n = 9). Patients underwent multimodal retinal imaging, including fundus photography, fundus autofluorescence (AF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA); in select cases, electroretinography as well as antiretinal and anti-retinal pigment epithelium (RPE) antibody testing were also used.Main outcomes and measuresClinical presentation and disease course.ResultsNine patients (8 [89%] female; mean [range] age, 43 [19-55] years) with acute retinopathy were identified in a cohort of 167 consecutive patients with PXE (frequency of 5%). Symptoms ranged from light sensations or metamorphopsia to profound vision loss. Visual acuity was reduced in 6 patients (67%), ranging from a best-corrected visual acuity of 20/30 to perception of hand movements at manifestation. All patients revealed characteristic fundus features with temporary appearance of partly confluent outer retinal whitish dots at the posterior pole, which corresponded to areas of hyperautofluorescence on fundus AF, loss of the ellipsoid band on OCT, and associated scotomata. The FA and late-phase ICGA imaging showed associated hyperfluorescence and hypocyanescence. Electroretinography revealed a variable reduction of amplitudes. Changes were fully reversible within 1 month in 3 of 8 patients with available follow-up data. Of the remaining 5 patients, 3 had a prolonged and likely permanent vision loss (observation period, 1-64 months) mainly owing to central subretinal hyperreflective material originating from angioid streaks. In 4 (67%) of 6 tested, antiretinal and/or anti-RPE antibodies were detected.Conclusions and relevanceAcute retinopathy in patients with PXE may occur, with symptoms ranging from short-term, reversible alterations to irreversible vision loss; these findings contribute to understanding the variable ocular disease progression in PXE and provide insights into the autoimmune phenomena of the posterior pole.

Project description:ObjectivePseudoxanthoma elasticum (PXE) is a multisystem heritable disorder caused by mutations in the Abcc6 gene. The disease is characterized by ectopic mineralization of the skin, eyes, and arterial blood vessels. Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis. The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization.MethodsWe used Abcc6 tm1JfK mice (Abcc6 -/- mice) as an established preclinical model of PXE. The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet (control group) and the atherogenic diet. Serum lipid profiles and bile acids were measured, and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay, respectively.ResultsAfter 50-58 weeks of feeding an atherogenic diet, the concentrations of total cholesterol, low-density lipoprotein/very-low-density lipoprotein cholesterol, and bile acids were significantly higher in the Abcc6 -/- mice on the atherogenic diet (180.9 ± 14.8 g/L, 145.9 ± 12.9 g/L, and 9.7 ± 1.4 μmol/L, respectively) than in Abcc6 -/- mice on a control diet (85.2 ± 4.8 g/L, 25.1 ± 5.5 g/L, and 3.3 ± 0.5 μmol/L, respectively) (P < 0.001). Hypercholesterolemia was accompanied by extensive lipid accumulation in the liver and aorta, a characteristic feature of steatosis. The direct calcium assay demonstrated significantly increased mineralization of the muzzle skin containing the dermal sheath of vibrissae (57.2 ± 4.4 μmol Ca/gram tissue on the atherogenic diet and 43.9 ± 2.2 μmol Ca/gram tissue on control diet; P < 0.01), a reproducible biomarker of the ectopic mineralization process in these mice. An increased frequency of mineralization was also observed in the kidneys and eyes of mice on the atherogenic diet (P < 0.01).ConclusionThese observations suggest that the atherogenic diet caused hypercholesterolemia and accelerated ectopic mineralization in the Abcc6 -/- mice. Our findings have clinical implications for patients with PXE, a currently intractable disorder with considerable morbidity and occasional mortality.

Dataset Information

A New Zebrafish Model for Pseudoxanthoma Elasticum.

Publications

A New Zebrafish Model for Pseudoxanthoma Elasticum.

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