Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing

Kimberly A Coughlan; Rajanikanth J Maganti; Andrea Frassetto; Christine M DeAntonis; meredith Wolfrom; Anne-Renee Graham; Shawn M Hillier; Steven Fortucci; Hoor Al Jandal; Sue-Jean Hong; Paloma H Giangrande; Paolo GV Martini

doi:10.24911/JBCGenetics/183-1542047633

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Original Article
Online Published: 05 Dec 2018

JBCGenetics. 2019; 2(1): 28-39

doi: 10.24911/JBCGenetics/183-1542047633

Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing

Kimberly A Coughlan, Rajanikanth J Maganti, Andrea Frassetto, Christine M DeAntonis, meredith Wolfrom, Anne-Renee Graham, Shawn M Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H Giangrande, Paolo GV Martini.

Abstract
Background: Primary Hyperoxaluria Type 1 (PH1) is an inborn error of metabolism caused by mutations in the AGXT gene, which encodes for the hepatocyte-specific enzyme alanine: glyoxylate aminotransferase (AGT). AGT catalyzes the conversion of glyoxylate to glycine in the peroxisome and prevents the build-up of oxalate which occurs in PH1. This causes nephrocalcinosis, systemic oxalosis, and end-stage renal disease. Liver transplant is currently the only curative treatment available. Although a mouse model has previously been generated, the severity of the reported disease phenotype varies, and a better understanding of the genotype-phenotype relationship in both the mouse model and human disease is needed.
Methods: We developed an Agxt-/- mouse model using CRISPR/Cas9-mediated gene editing. We performed a natural history study and ethylene glycol (EG) challenge to evaluate the phenotype of this mouse.
Results: Agxt-/- mice had elevated plasma glycolate, urine glycolate, and urine oxalate levels compared to Agxt+/+ mice. A small subset of Agxt-/- mice developed minimal nephrocalcinosis (1/8 at 12 weeks, 1/8 at 26 weeks, 0/8 at 39 weeks, and 3/7 at 52 weeks of age). When challenged with 0.7% or 1.2% EG in drinking water for 3 weeks, 2/10 Agxt-/- mice developed nephrocalcinosis. Agxt2mRNA and protein expression were unchanged between Agxt-/- and Agxt+/+ mice. Hydroxy acid oxidase 1(Hao1) messenger ribonucleic acid (mRNA) levels were unchanged, but the corresponding glycolate oxidase protein was increased in Agxt-/- mice.
Conclusion: We have created an Agxt-/- mouse model which resembles much of the clinical phenotype of PH1 patients and will be a useful tool in developing novel therapies for this devastating disease.

Key words: Primary Hyperoxaluria Type 1, CRISPR/Cas9, nephrocalcinosis, inborn error of metabolism

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Pubmed Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom m, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG, . Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. 2019; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Web Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom m, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG, . Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. https://www.jbcgenetics.com/?mno=16869 [Access: November 14, 2024]. doi:10.24911/JBCGenetics/183-1542047633

AMA (American Medical Association) Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom m, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG, . Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. 2019; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Vancouver/ICMJE Style

Coughlan KA, Maganti RJ, Frassetto A, DeAntonis CM, Wolfrom m, Graham A, Hillier SM, Fortucci S, Jandal HA, Hong S, Giangrande PH, Martini PG, . Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics. (2019), [cited November 14, 2024]; 2(1): 28-39. doi:10.24911/JBCGenetics/183-1542047633

Harvard Style

Coughlan, K. A., Maganti, R. J., Frassetto, A. ., DeAntonis, C. M., Wolfrom, m. ., Graham, A. ., Hillier, S. M., Fortucci, S. ., Jandal, H. . A., Hong, S. ., Giangrande, P. H., Martini, P. G. & (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. JBCGenetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633

Turabian Style

Coughlan, Kimberly A, Rajanikanth J Maganti, Andrea Frassetto, Christine M DeAntonis, meredith Wolfrom, Anne-Renee Graham, Shawn M Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H Giangrande, Paolo GV Martini, and . 2019. Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. Journal of Biochemical and Clinical Genetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633

Chicago Style

Coughlan, Kimberly A, Rajanikanth J Maganti, Andrea Frassetto, Christine M DeAntonis, meredith Wolfrom, Anne-Renee Graham, Shawn M Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H Giangrande, Paolo GV Martini, and . "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." Journal of Biochemical and Clinical Genetics 2 (2019), 28-39. doi:10.24911/JBCGenetics/183-1542047633

MLA (The Modern Language Association) Style

Coughlan, Kimberly A, Rajanikanth J Maganti, Andrea Frassetto, Christine M DeAntonis, meredith Wolfrom, Anne-Renee Graham, Shawn M Hillier, Steven Fortucci, Hoor Al Jandal, Sue-Jean Hong, Paloma H Giangrande, Paolo GV Martini, and . "Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing." Journal of Biochemical and Clinical Genetics 2.1 (2019), 28-39. Print. doi:10.24911/JBCGenetics/183-1542047633

APA (American Psychological Association) Style

Coughlan, K. A., Maganti, R. J., Frassetto, A. ., DeAntonis, C. M., Wolfrom, m. ., Graham, A. ., Hillier, S. M., Fortucci, S. ., Jandal, H. . A., Hong, S. ., Giangrande, P. H., Martini, P. G. & (2019) Generation of a mouse model of Primary Hyperoxaluria Type 1 via CRISPR/Cas9 mediated gene editing. Journal of Biochemical and Clinical Genetics, 2 (1), 28-39. doi:10.24911/JBCGenetics/183-1542047633

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