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Generation and validation of a complete knockout model of abcc6a in zebrafish

Matthias Van Gils (UGent) , Andy Willaert (UGent) , Eva De Vilder (UGent) , Paul Coucke (UGent) and Olivier Vanakker (UGent)
(2018) JOURNAL OF INVESTIGATIVE DERMATOLOGY. 138(11). p.2333-2342
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Abstract
Pseudoxanthoma elasticum is an ectopic mineralization disease due to biallelic ABCC6 mutations. As no treatment options are currently available, a reliable zebrafish model is invaluable for high throughput compound screening. However, data from previously reported knockdown and mutant zebrafish models for abcc6a, the functional orthologue of ABCC6, showed phenotypic discrepancies. To address this, we developed a complete abcc6a knockout model using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 and compared its phenotype to that of a mutant model (Sa963) and a splice junction morpholino model. Our data showed that abcc6a is not required for embryonic survival, but rather that it has an essential role in controlling mineralization. The three models developed very similar hypermineralization of spine and ribs starting embryonically and progressing in adulthood with development of scoliosis. Our results indicate a direct relation between loss of abcc6a expression and dysregulated osteogenesis. As such, our models recapitulate part of the human phenotype in which ectopic mineralization and pro-osteogenic signaling have been reported. Because of its reproducibility in three models and its ease of quantification, we consider this phenotype to be unequivocally the result of abcc6 deficiency and, as such, an excellent readout for drug screening purposes and multiplex mutagene analysis.
Keywords
PSEUDOXANTHOMA ELASTICUM, ECTOPIC MINERALIZATION, GENOME, SYSTEM, PXE

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Chicago
Van Gils, Matthias, Andy Willaert, Eva De Vilder, Paul Coucke, and Olivier Vanakker. 2018. “Generation and Validation of a Complete Knockout Model of Abcc6a in Zebrafish.” Journal of Investigative Dermatology 138 (11): 2333–2342.
APA
Van Gils, M., Willaert, A., De Vilder, E., Coucke, P., & Vanakker, O. (2018). Generation and validation of a complete knockout model of abcc6a in zebrafish. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 138(11), 2333–2342.
Vancouver
1.
Van Gils M, Willaert A, De Vilder E, Coucke P, Vanakker O. Generation and validation of a complete knockout model of abcc6a in zebrafish. JOURNAL OF INVESTIGATIVE DERMATOLOGY. 2018;138(11):2333–42.
MLA
Van Gils, Matthias et al. “Generation and Validation of a Complete Knockout Model of Abcc6a in Zebrafish.” JOURNAL OF INVESTIGATIVE DERMATOLOGY 138.11 (2018): 2333–2342. Print.
@article{8571542,
  abstract     = {Pseudoxanthoma elasticum is an ectopic mineralization disease due to biallelic ABCC6 mutations. As no treatment options are currently available, a reliable zebrafish model is invaluable for high throughput compound screening. However, data from previously reported knockdown and mutant zebrafish models for abcc6a, the functional orthologue of ABCC6, showed phenotypic discrepancies. To address this, we developed a complete abcc6a knockout model using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 and compared its phenotype to that of a mutant model (Sa963) and a splice junction morpholino model. Our data showed that abcc6a is not required for embryonic survival, but rather that it has an essential role in controlling mineralization. The three models developed very similar hypermineralization of spine and ribs starting embryonically and progressing in adulthood with development of scoliosis. Our results indicate a direct relation between loss of abcc6a expression and dysregulated osteogenesis. As such, our models recapitulate part of the human phenotype in which ectopic mineralization and pro-osteogenic signaling have been reported. Because of its reproducibility in three models and its ease of quantification, we consider this phenotype to be unequivocally the result of abcc6 deficiency and, as such, an excellent readout for drug screening purposes and multiplex mutagene analysis.},
  author       = {Van Gils, Matthias and Willaert, Andy and De Vilder, Eva and Coucke, Paul and Vanakker, Olivier},
  issn         = {0022-202X},
  journal      = {JOURNAL OF INVESTIGATIVE DERMATOLOGY},
  language     = {eng},
  number       = {11},
  pages        = {2333--2342},
  title        = {Generation and validation of a complete knockout model of abcc6a in zebrafish},
  url          = {http://dx.doi.org/10.1016/j.jid.2018.06.183},
  volume       = {138},
  year         = {2018},
}

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