PONE-D-23-22545Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorumPLOS ONE

Dear Dr.Sproule,

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Although neither one of the reviewers suggested additional experiments, reviewer 2 felt - and I agree - that the manuscript could benefit from streamlining including shortening of the text and restructuring of data presentation. Several additional points raised need clarification and consideration.

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper extends the authors' efforts to clarify the genetic modifications affecting epidermolysis bullosa (EB) using mouse models. The authors focus on Dst and demonstrate that mutations in Dst exon 23 can protect the junctional EB (JEB) phenotype. Through their analyses, the authors rediscover the rodless Dst isoform and find that removal of the pinnae can ameliorate EB skin phenotypes in mice. The study is well-conducted and informative. I have some comments as follows:

1) In some figures, B6 is used to represent Lamc2wt/wt, but in others, B6 stands for Lamc2jeb/jeb. Consistency in nomenclature across all figures would be preferable.

2) The rediscovery of the rodless Dst1 isoform is intriguing. Please emphasize that the removal of exon 23 is in-frame, enabling readers to more readily understand that exon 23 skipping does not lead to nonsense-mediated mRNA decay.

3) Is it possible that pinnae removal could improve inflammatory phenotypes observed in other EB model mice (e.g., Lama3 targeted disruption; PMID 27729280)? If so, please make a note of it in the manuscript.

Reviewer #2: This study presents mouse models of dystonin-associated epidermolysis bullosa simplex and also from these models implicates dystonin as a modifier of laminin-332-associated junctional epidermolysis bullosa. It is a well-conducted, comprehensive work. The presented findings are highly interesting and will be of importance for our understanding of dystonin biology, epidermolysis bullosa and the models will be useful for therapy research.

The manuscript is very rich in data and this makes it a quite challenging read. In addition, some findings are limitedly supported due to few mice or biological replicates analyzed. In my opinion the work would greatly benefit from restructuring the manuscript to focus on the key findings and findings of more supportive nature or other interesting observations deserve to be kept but I think that they could just be shortly mentioned and the data and more detailed explanation of them presented as supporting information. 12 figures are to much for the reader to effectively take in.

In the introduction it is stated in regard to modifiers of disease in epidermolysis bullosa (lines 46-48) that no additional modifiers apart from MMP1 have been identified. This statement is in my opinion too strong. There has been associations in patients made of higher decorin expression and milder diseases in recessive dystrophic epidermolysis bullosa (Odorisio et al., Human Mol Genet 2014), a similar link was made for PRELP (Chacon-Solano et al., Matrix Biol 2022).

The correct abbreviation for laminin-332 is LM332.

The observations of pinnae removal delaying development of severe phenotypes and extending healthy span are interesting. The suggestion that is secondary due to reduced scratching of ears is reasonable. However, did the authors also consider autoimmunity?

The discussion is interesting but I think it is too long to be effective. I would recommend to shorten it an focus on discussing essential findings.

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Reviewer #1: No

Reviewer #2: No

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Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorum

PONE-D-23-22545R1

Dear Dr. Sproule,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication. One of the reviewers found the manuscript could still be further streamlined but there was no opposition to acceptance. The manuscript will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Gerhard Wiche, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Thank you for revising the manuscript and considering my suggestions.

The preferred abbreviation for laminin is LM (Aumailley et al., 2005 - A simplified laminin nomenclature doi: 10.1016/j.matbio.2005.05.006). However, you are of course free to use any abbreviation you like. This is not the reason to why I am recommending another round of revisions. I think that the findings are highly interesting, however, there is still a lack of streamlining and prioritization of data which make the manuscript challenging to read. 12 main figures are not optimal for a study like this. I would highly recommend you to perform additional streamlining of the manuscript.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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