Spontaneous asj-2J Mutant Mouse as a Model for Generalized Arterial Calcification of Infancy: A Large Deletion/Insertion Mutation in the Enpp1 Gene.

Authors

Qiaoli Li, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical CollegeFollow
C Herbert Pratt, Jackson Laboratory, United States of AmericaBar Harbor, MEFollow
Louise A Dionne, Jackson Laboratory, United States of AmericaBar Harbor, ME
Heather Fairfield, Jackson Laboratory, United States of AmericaBar Harbor, ME
Son Yong Karst, Jackson Laboratory, United States of AmericaBar Harbor, ME
John P Sundberg, Jackson Laboratory, United States of AmericaBar Harbor, MEFollow
Jouni Uitto, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical CollegeFollow
Yin Tintut, University of California, Los Angeles, Department of Medicine

Document Type

Article

Publication Date

12-5-2014

Comments

This article has been peer reviewed. It was published in: PLoS One.

Volume 9, Issue 12, 5 December 2014, Article number e113542.

The published version is available at DOI: 10.1371/journal.pone.0113542

Copyright © 2014 Li et al.

Abstract

Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder caused by mutations in the ENPP1 gene, manifests with extensive mineralization of the cardiovascular system. The affected individuals in most cases die within the first year of life, and there is currently no effective treatment for this disorder. In this study, we characterized a spontaneous mutant mouse, asj-2J, as a model for GACI. These mice were identified as part of a phenotypic deviant search in a large-scale production colony of BALB/cJ mice at The Jackson Laboratory. They demonstrated a characteristic gait due to stiffening of the joints, with phenotypic similarity to a previously characterized asj ("ages with stiffened joints") mouse, caused by a missense mutation in the Enpp1 gene. Complementation testing indicated that asj-2J and asj were allelic. PCR-based mutation detection strategy revealed in asj-2J mice a large, 40,035 bp, deletion spanning from intron 1 to the 3'-untranslated region of the Enpp1 gene, coupled with a 74 bp insertion. This was accompanied with a significant reduction in the plasma PPi concentration and reduced PPi/Pi ratio. As a consequence, extensive aberrant mineralization affecting the arterial vasculature, a number of internal organs, and the dermal sheath of vibrissae, a progressive biomarker of the ectopic mineralization process, was demonstrated by a combination of micro computed tomography, histopathology with calcium-specific stains, and direct chemical assay of calcium. Comparison of the asj and asj-2J mice demonstrated that the latter ones, particularly when placed on an acceleration diet high in phosphate and low in magnesium, had more extensive mineralization. Thus, the asj-2J mouse serves as a novel model for GACI, a currently intractable disorder.

Recommended Citation

Li, Qiaoli; Pratt, C Herbert; Dionne, Louise A; Fairfield, Heather; Karst, Son Yong; Sundberg, John P; Uitto, Jouni; and Tintut, Yin, "Spontaneous asj-2J Mutant Mouse as a Model for Generalized Arterial Calcification of Infancy: A Large Deletion/Insertion Mutation in the Enpp1 Gene." (2014). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 39.
https://jdc.jefferson.edu/dcbfp/39

PubMed ID

25479107