Title

Quantitative Trait Locus and Integrative Genomics Revealed Candidate Modifier Genes for Ectopic Mineralization in Mouse Models of Pseudoxanthoma Elasticum.

Document Type

Article

Publication Date

12-1-2019

Keywords

JMG

JAX Source

J Invest Dermatol 2019 Dec; 139(12):2447-2457.e7

PMID

31207231

DOI

https://doi.org/10.1016/j.jid.2019.04.023

Grant

AA108776,CA034196

Abstract

Pseudoxanthoma elasticum, a prototype of heritable multisystem ectopic mineralization disorders, is caused by mutations in the ABCC6 gene encoding a putative efflux transporter, ABCC6. The phenotypic spectrum of pseudoxanthoma elasticum varies, and the correlation between genotype and phenotype has not been established. To identify genetic modifiers, we performed quantitative trait locus analysis in inbred mouse strains that carry the same hypomorphic allele in Abcc6 yet with highly variable ectopic mineralization phenotypes of pseudoxanthoma elasticum. Abcc6 was confirmed as a major determinant for ectopic mineralization in multiple tissues. Integrative analysis using functional genomics tools that included GeneWeaver, String, and Mouse Genome Informatics identified a total of nine additional candidate modifier genes that could influence the organ-specific ectopic mineralization phenotypes. Integration of the candidate genes into the existing ectopic mineralization gene network expands the current knowledge on the complexity of the network that, as a whole, governs ectopic mineralization in soft connective tissues.

Comments

The authors thank Dian Wang, Joshua Kingman, Jeffrey Lamont, Wenning Qin, Linda Siracusa, Jieyu Zhang, Jingyi Zhao, Victoria E. Kennedy, and Kathleen A. Silva for their technical assistance.

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