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JMG, Animals, Mice, Epidermolysis Bullosa, Junctional, Non-Fibrillar Collagens, Collagen, Mutation, Amino Acids







This work was supported by grants from DeBRA Austria (DCR) and DeBRA International (DCR), National Institutes of Health (NIH) grant number OD011190 (MVW), NIH grant numbers DP1 GM105378 (JKJ) and NIH R01 GM088040 (JKJ), the Jim and Ann Orr MGH Research Scholar Award (JKJ), and by The Jackson Laboratory (DCR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Previous work strongly implicated Collagen 17a1 (Col17a1) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation (Lamc2jeb) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2-3 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S/G and 1277 N/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of Lamc2jeb/jeb JEB. Together these studies exploiting gene editing to functionally dissect the Col17a1 modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous 'healthy' alleles in other genes.


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