Document Type
Article
Publication Date
1-1-2023
Original Citation
Sproule TJ,
Philip VM,
Chaudhry N,
Roopenian DC,
Sundberg J.
Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice. PLoS One. 2023;18(7):e0288263.
Keywords
JMG, Animals, Mice, Epidermolysis Bullosa, Junctional, Skin, Blister, Epidermis, Quantitative Trait Loci
JAX Source
PLoS One. 2023;18(7):e0288263.
ISSN
1932-6203
PMID
37437067
DOI
https://doi.org/10.1371/journal.pone.0288263
Grant
DCR received awards ’Roopenian 1’ from Debra UK (https://www.debra.org.uk/) and ’Roopenian 2’ from Debra Austria (https://www. debra-austria.org/). The Jackson Laboratory (jax. org) provided supplemental support for these studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Abstract
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
Comments
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.