The abcc6a Gene Expression Is Required for Normal Zebrafish Development

Li, Qiaoli; Sadowski, Sara; Frank, Michael; Chai, Chun-Li; Váradi, András; Ho, Shiu Ying; Li, Hong; Dean, Michael; Thisse, Christine; Thisse, Bernard; Uitto, Jouni

doi:10.1038/jid.2010.174

Cited by 43 publications

(62 citation statements)

References 31 publications

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“…There may sometimes be difficulty in distinguishing some missense mutations from inconsequential polymorphisms, but a recently developed mRNA phenotypic rescue assay in zebrafish can assist in distinguishing between these two possibilities [33,34]. There are, to our knowledge, no cases in which the presence of two mutations in the ABCC6 gene has not been associated with clinical findings of PXE in individuals older than 30 years of age.…”

Section: Diagnosis and Classificationmentioning

confidence: 99%

Pseudoxanthoma elasticum: diagnostic features, classification and treatment options

Uitto¹,

Jiang²,

Váradi

et al. 2014

Expert Opinion on Orphan Drugs

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Introduction Pseudoxanthoma elasticum (PXE), a multisystem orphan disease, clinically affects the skin, the eyes, and the cardiovascular system with considerable morbidity and mortality. The clinical manifestations reflect the underlying pathology consisting of ectopic mineralization of peripheral connective tissues. Areas Covered The diagnostic criteria of PXE include characteristic clinical findings, together with histopathology of accumulation of pleiomorphic elastic structures in the dermis with progressive mineralization, and the presence of mutations in the ABCC6 gene. PXE-like cutaneous changes can also be encountered in other ectopic mineralization disorders, including generalized arterial calcification of infancy (GACI) caused by mutations in the ENPP1 gene. In some cases, overlapping clinical features of PXE/GACI, associated with mutations either in ABCC6 or ENPP1, have been noted. PXE demonstrates considerable inter- and intrafamilial heterogeneity, and consequently, accurate diagnosis is required for appropriate classification with prognostic implications. There is no effective and specific treatment for the systemic manifestations of PXE, but effective therapies to counteract the ocular complications are in current clinical use. Expert Opinion A number of observations in the murine model, the Abcc6−/− mouse, have indicated that the mineral composition of diet, particularly the magnesium content, can influence the severity of the mineralization phenotype. These observations suggest that appropriate dietary interventions, coupled with lifestyle modifications, including smoking cessation, might alleviate the symptoms and improve the quality of life of individuals affected with this, currently intractable, orphan disease.

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Section: Diagnosis and Classificationmentioning

confidence: 99%

Pseudoxanthoma elasticum: diagnostic features, classification and treatment options

Uitto¹,

Jiang²,

Váradi

et al. 2014

Expert Opinion on Orphan Drugs

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show abstract

“…Similarly, KO mice, in which the Abcc6 gene has been inactivated by targeted ablation, characteristic mineralization is not evident until at 5–6 weeks of life (Jiang et al, 2007, 2009). Injection of the abcc6a morpholino in the zebrafish resulted in a early phenotype of pericardial edema and curled tail, associated with death by 8 dpf, but there was no evidence of ectopic mineralization at this stage (Li et al, 2010). The mineralization phenotype, if developmentally corresponding to human or mouse pathogenesis of PXE, might occur later in life.…”

Section: Morpholino Knockdown Of Zebrafish Gene Expressionmentioning

confidence: 99%

“…For example, the overall sequence homology at the amino acid level between the human and zebrafish ABCC6 genes is 47 percent, yet certain critical domains, such as the nucleotide binding folds, indispensable for the function of this transmembrane efflux transporter, are conserved by ~60 percent (Li et al, 2010). …”

Section: The Zebrafish Genomementioning

confidence: 99%

“…Similarly, the efficacy of 100 percent of a morpholino placed on the exon 18/intron 19 junction of the abcc6b gene is illustrated in Fig. 3 (Li et al, 2010). …”

Section: Morpholino Knockdown Of Zebrafish Gene Expressionmentioning

confidence: 99%

“…The mineralization phenotype, if developmentally corresponding to human or mouse pathogenesis of PXE, might occur later in life. Therefore, the discordance between the zebrafish phenotypes with that in human and mouse, raises the possibility that the ABCC6 gene products might have different biological functions depending on the species, in which case the abcc6 knockdown in zebrafish is not an appropriate model for PXE (Li et al, 2010). …”

Section: Morpholino Knockdown Of Zebrafish Gene Expressionmentioning

confidence: 99%

See 2 more Smart Citations

Zebrafish: A Model System to Study Heritable Skin Diseases

Frank

Thisse

et al. 2011

Journal of Investigative Dermatology

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Heritable skin diseases represent a broad spectrum of clinical manifestations due to mutations in ~500 different genes. A number of model systems have been developed to advance our understanding of the pathomechanisms of genodermatoses. Zebrafish (Danio rerio), a freshwater vertebrate, has a well-characterized genome, the expression of which can be easily manipulated. The larvae develop rapidly, with all major organs having developed by 5–6 days post fertilization, including the skin, consisting of the epidermis comprising two cell layers and separated from the dermal collagenous matrix by a basement membrane. This perspective highlights the morphologic and ultrastructural features of zebrafish skin, in the context of cutaneous gene expression. These observations suggest that zebrafish provides a useful model system to study molecular aspects of skin development, as well as the pathogenesis and treatment of select heritable skin diseases.

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From membrane to mineralization: the curious case of the ABCC6 transporter

et al. 2020

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ATP‐binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP‐dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.

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The abcc6a Gene Expression Is Required for Normal Zebrafish Development

Cited by 43 publications

References 31 publications

Pseudoxanthoma elasticum: diagnostic features, classification and treatment options

Pseudoxanthoma elasticum: diagnostic features, classification and treatment options

Zebrafish: A Model System to Study Heritable Skin Diseases

From membrane to mineralization: the curious case of the ABCC6 transporter

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