scholarly journals A New Zebrafish Model for Pseudoxanthoma Elasticum

2021 ◽  
Vol 9 ◽  
Author(s):  
Dávid Czimer ◽  
Klaudia Porok ◽  
Dániel Csete ◽  
Zsolt Gyüre ◽  
Viktória Lavró ◽  
...  
Keyword(s):  
Genetic Disease ◽  
Genetic Factors ◽  
Soft Tissues ◽  
Biological Process ◽  
Pseudoxanthoma Elasticum ◽  
Zebrafish Genome ◽  
Ectopic Calcification ◽  
Therapeutic Approaches ◽  
Zebrafish Model ◽  
Significant Health

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.

scholarly journals ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

2021 ◽  
Vol 22 (9) ◽  
pp. 4555
Author(s):  
Briana K. Shimada ◽  
Viola Pomozi ◽  
Janna Zoll ◽  
Sheree Kuo ◽  
Ludovic Martin ◽  
...  
Keyword(s):  
Soft Tissues ◽  
Genetic Disorders ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Ectopic Calcification ◽  
Direct Inhibition ◽  
Inorganic Pyrophosphate ◽  
Cardiovascular Tissues ◽  
Ectopic Mineralization

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

scholarly journals Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 278
Author(s):  
Jianjian Sun ◽  
Peilu She ◽  
Xu Liu ◽  
Bangjun Gao ◽  
Daqin Jin ◽  
...  
Keyword(s):  
Vitamin K ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Pseudoxanthoma Elasticum ◽  
Matrix Gla Protein ◽  
Ectopic Calcification ◽  
Transcription Activator ◽  
Multisystem Disorder ◽  
Ectopic Mineralization ◽  
Extensive Calcification

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch’s membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.

Social Dimensions of Genetic Disorders

1992 ◽  
Vol 14 (1) ◽  
pp. 10-13 ◽  
Author(s):  
Joan Ablon
Keyword(s):  
Health Education ◽  
Infant Mortality ◽  
Genetic Disease ◽  
Genetic Factors ◽  
Genetic Disorders ◽  
Genetic Defects ◽  
Social Dimensions ◽  
Live Births ◽  
Department Of Health ◽  
Recessive Genes

Each of us carries between 4-8 recessive genes for serious genetic defects, and, hence, stands a statistical chance of passing on a serious or lethal condition to each child… 12 million Americans carry true genetic disease due wholly or partly to defective genes or chromosomes…40 percent or more of all infant mortality results from genetic factors…4.8 to 5 percent of all live births have genetic defects. (U.S. Department of Health, Education, and Welfare. "What are the Facts About Genetic Disease?" National Inst. of Gen. Med. Scs., P.H.S., N.I.H. DHEW Pub. No. (NIH), 75-370, 1975.)

scholarly journals Similarly Lethal Strains of Extraintestinal Pathogenic Escherichia coli Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

mSphere ◽  
2016 ◽  
Vol 1 (2) ◽  
Author(s):  
Amelia E. Barber ◽  
Brittany A. Fleming ◽  
Matthew A. Mulvey
Keyword(s):  
The United States ◽  
Host Responses ◽  
Inflammatory Condition ◽  
Therapeutic Approaches ◽  
Zebrafish Model ◽  
Life Threatening ◽  
High Degree ◽  
Care Costs ◽  
Variable Impact ◽  
Degree Of Heterogeneity

ABSTRACT Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In the United States, sepsis due to ExPEC and other pathogens kills well over a quarter of a million people each year and is associated with tremendous health care costs. A high degree of heterogeneity in the signs and symptomology of sepsis makes this disease notoriously difficult to effectively diagnose and manage. Here, using a zebrafish model of sepsis, we find that similarly lethal but genetically distinct ExPEC isolates can elicit notably disparate host responses. These variances are in part due to differences in the levels and types of flagellin that are expressed by the infecting ExPEC strains. A better understanding of the variable impact that bacterial factors like flagellin have on host responses during sepsis could lead to improved diagnostic and therapeutic approaches to these often deadly infections. In individuals with sepsis, the infecting microbes are commonly viewed as generic inducers of inflammation while the host background is considered the primary variable affecting disease progression and outcome. To study the effects of bacterial strain differences on the maladaptive immune responses that are induced during sepsis, we employed a novel zebrafish embryo infection model using extraintestinal pathogenic Escherichia coli (ExPEC) isolates. These genetically diverse pathogens are a leading cause of sepsis and are becoming increasingly dangerous because of the rise of multidrug-resistant strains. Zebrafish infected with ExPEC isolates exhibit many of the pathophysiological features seen in septic human patients, including dysregulated inflammatory responses (cytokine storms), tachycardia, endothelial leakage, and progressive edema. However, only a limited subset of ExPEC isolates can trigger a sepsis-like state and death of the host when introduced into the bloodstream. Mirroring the situation in human patients, antibiotic therapy reduced ExPEC titers and improved host survival rates but was only effective within limited time frames that varied, depending on the infecting pathogen. Intriguingly, we find that phylogenetically distant but similarly lethal ExPEC isolates can stimulate markedly different host transcriptional responses, including disparate levels of inflammatory mediators. These differences correlate with the amounts of bacterial flagellin expression during infection, as well as differential activation of Toll-like receptor 5 by discrete flagellar serotypes. Altogether, this work establishes zebrafish as a relevant model of key aspects of human sepsis and highlights the ability of genetically distinct ExPEC isolates to induce divergent host responses independently of baseline host attributes. IMPORTANCE Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In the United States, sepsis due to ExPEC and other pathogens kills well over a quarter of a million people each year and is associated with tremendous health care costs. A high degree of heterogeneity in the signs and symptomology of sepsis makes this disease notoriously difficult to effectively diagnose and manage. Here, using a zebrafish model of sepsis, we find that similarly lethal but genetically distinct ExPEC isolates can elicit notably disparate host responses. These variances are in part due to differences in the levels and types of flagellin that are expressed by the infecting ExPEC strains. A better understanding of the variable impact that bacterial factors like flagellin have on host responses during sepsis could lead to improved diagnostic and therapeutic approaches to these often deadly infections. Podcast: A podcast concerning this article is available.

scholarly journals Engineered osteoclasts as living treatment materials for heterotopic ossification therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenjing Jin ◽  
Xianfeng Lin ◽  
Haihua Pan ◽  
Chenchen Zhao ◽  
Pengcheng Qiu ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Soft Tissues ◽  
Ectopic Calcification ◽  
Calcified Tissue ◽  
Restricted Activity ◽  
Calcium Minerals ◽  
Reliable Methods ◽  
Poor Adhesion

AbstractOsteoclasts (OCs), the only cells capable of remodeling bone, can demineralize calcium minerals biologically. Naive OCs have limitations for the removal of ectopic calcification, such as in heterotopic ossification (HO), due to their restricted activity, migration and poor adhesion to sites of ectopic calcification. HO is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these unexpected calcified plaques. In the present study, we develop a chemical approach to modify OCs with tetracycline (TC) to produce engineered OCs (TC-OCs) with an enhanced capacity for targeting and adhering to ectopic calcified tissue due to a broad affinity for calcium minerals. Unlike naive OCs, TC-OCs are able to effectively remove HO both in vitro and in vivo. This achievement indicates that HO can be reversed using modified OCs and holds promise for engineering cells as “living treatment agents” for cell therapy.

scholarly journals Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC

2016 ◽  
Vol 9 (458) ◽  
pp. ra121-ra121 ◽  
Author(s):  
H. Jin ◽  
C. St. Hilaire ◽  
Y. Huang ◽  
D. Yang ◽  
N. I. Dmitrieva ◽  
...  
Keyword(s):  
Genetic Disease ◽  
Ectopic Calcification ◽  
Increased Activity

scholarly journals Editorial: Special Issue on “Therapeutic Approaches for Cystic Fibrosis”

2020 ◽  
Vol 21 (18) ◽  
pp. 6657
Author(s):  
Nicoletta Pedemonte
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disease ◽  
Special Issue ◽  
Therapeutic Approaches ◽  
Editorial Special Issue

Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasian populations, occurring in approximately 1 in 3000 newborns worldwide [...]

Atypical presentation of pseudoxanthoma elasticum with abdominal cutis laxa: Evidence for a spectrum of ectopic calcification disorders?

2011 ◽  
Vol 155 (11) ◽  
pp. 2855-2859 ◽  
Author(s):  
Olivier M. Vanakker ◽  
Bart P. Leroy ◽  
Leon J. Schurgers ◽  
Cees Vermeer ◽  
Paul J. Coucke ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Cutis Laxa ◽  
Ectopic Calcification ◽  
Atypical Presentation

scholarly journals Harlequin ichthyosis - a rare genetic disorder : a case report

2015 ◽  
Vol 04 (04) ◽  
pp. 199-201
Author(s):  
Arnab Ghosh ◽  
B C Dutta ◽  
Sudipta Pal
Keyword(s):  
Case Report ◽  
Life Expectancy ◽  
Genetic Disease ◽  
Genetic Factors ◽  
Genetic Disorder ◽  
Treatment Protocol ◽  
Present Treatment ◽  
Harlequin Ichthyosis ◽  
Micro Anatomy ◽  
Affected Infant

AbstractHarlequin lchthyosis(HI) is a type of genodermatosis. It is a rare and fatal genetic disease. Life expectancy in an affected infant is only a few days. The defect lies in mutation of ABCA12 gene. The barrier action of skin is severely compromised making the infant prone to infections and dehydration. Present treatment protocol consists mainly of conservative and supportive therapies. The authors report this case as it is a rare disease. The main purpose of this report is to create awareness about the disease and discuss the genetic factors along with micro anatomy of skin ultimately leading to this condition.

scholarly journals Fishing for gene function – endocrine modelling in the zebrafish

2006 ◽  
Vol 189 (3) ◽  
pp. 425-439 ◽  
Author(s):  
I M McGonnell ◽  
R C Fowkes
Keyword(s):  
Gene Function ◽  
Endocrine System ◽  
Zebrafish Genome ◽  
Reverse Genetic ◽  
Vertebrate Development ◽  
Zebrafish Model ◽  
The Past ◽  
Disease States ◽  
Endocrine Organs ◽  
Genetic Techniques

The use of zebrafish (Danio rerio) in scientific research is growing rapidly. It initially became popular as a model of vertebrate development because zebrafish embryos develop rapidly and are transparent. In the past 5 years, the sequencing of the zebrafish genome has increased the profile of zebrafish research even further, expanding into other areas such as pharmacology, cancer research and drug discovery. The use of zebrafish in endocrine research has mainly been confined to the study of the development of endocrine organs. However, it is likely to be a useful model in other areas of endocrinology, as there are a wide variety of both forward and reverse genetic techniques that can be employed in the zebrafish to decipher gene function in disease states. In this review, we compare the endocrine system of the zebrafish to mouse and human, demonstrating that the systems are sufficiently similar for zebrafish to be employed as a model for endocrine research. We subsequently review the repertoire of genetic techniques commonly employed in the zebrafish model to understand gene function in vertebrate development and disease. We anticipate that the use of these techniques will make the zebrafish a prominent model in endocrine research in the coming years.

Sign in / Sign up

Export Citation Format

Share Document