Identification of coexisting Mfrprd6 and Pde6brd10 mutations causing spontaneous retinal detachment in commercially available rd6 mice

Asaka Lee Shiozawa; Maika Hosoi Kobayashi; Yusuke Shiozawa; Yasuhiro Ikeda; Yoshitaka Miyagawa; Fumiki Okamoto; Mashito Sakai; Takashi Okada; Tsutomu Igarashi

doi:10.1371/journal.pone.0332446

Peer Review History

Original SubmissionApril 26, 2025
1 Jul 2025 Decision Letter - Tatsuya Inoue, Editor PONE-D-25-22608Identification of coexisting Mfrprd6 and Pde6brd10 mutations causing spontaneous retinal detachment in commercially available rd6 micePLOS ONE Dear Dr. Igarashi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 15 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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 ****** 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 study provides valuable insights, but there are concerns regarding the results. The results section does not directly mention electroretinography (ERG) or histopathology in rd10 mice, but the discussion section does mention ERG and histopathology in rd10 mice. Based on the results of whole genome sequencing, etc., does this mean that all rd6-RD mice have the Pde6 rd10/rd10 mutation? Reviewer #2: When working with spontaneously occurring animal models, it is essential to remain alert to the possibility of additional pathogenic mutations beyond those already reported. This manuscript underscores the previously unrecognized presence of the rd10 mutation in commercially available rd6 mice, delivering an important cautionary message to researchers who rely on this model. Both the experimental design and the overall presentation are clear and persuasive. My primary concern is that the conclusion—that severe retinal degeneration and retinal detachment in the rd6RD line arise from a combination of rd6 and rd10 mutations—is based solely on short-read whole-genome sequencing (WGS) data from a single mouse family. Because the Pde6b (c.1678C>T, p.R560C) mutation can be readily verified by Sanger sequencing, expanding the analysis to a larger cohort of animals would greatly strengthen the evidence. In addition, since rd10 mice are commercially available, crossing them with rd6 mice lacking the Pde6b mutation would test whether the rd6RD phenotype is truly reproducible, further enhancing the robustness of the conclusions. ****** 6. 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 ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0332446.r001
Revision 1
9 Jul 2025 Author Response Journal Requirements: 1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response: According to manuscript body formatting guidelines, we checked and created our manuscript. 2. To comply with PLOS ONE submissions requirements, in your Methods section, please provide additional information regarding the experiments involving animals and ensure you have included details on (1) methods of sacrifice, (2) methods of anesthesia and/or analgesia, and (3) efforts to alleviate suffering. Response: According to the experiments involving animals, we added the sentence. (1) methods of sacrifice; We added “Exsanguination was performed under deep anesthesia induced by ketamine/xylazine as the method of euthanasia.” in Animal husbandry. (2) methods of anesthesia and/or analgesia; We added “Mice were treated with an intraperitoneal administration of a combination of ketamine (Daiichi Sankyo Co., Ltd., Tokyo, Japan) and xylazine (Bayer Medical, Ltd., Tokyo, Japan) at 100 and 10 mg/kg body weight, respectively.” in Animal husbandry. (3) efforts to alleviate suffering; To ensure ethical approval and adherence to guidelines, the approval number from the institutional animal care and use committee and the name of the applicable guidelines are provided in the Animal husbandry section. 3. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript. Response: All funding-related information has been deleted from the manuscript text. 4. We note that your Data Availability Statement is currently as follows: All relevant data are within the manuscript and in Supporting Information files. - The values behind the means, standard deviations and other measures reported; - The values used to build graphs; Response: The values used to generate the graphs in Fig. 3b, Fig. 5c, and Fig. 6c are summarized in a list (S2 Table). We have added a title to S2 Table in the Supporting Information. - The points extracted from images for analysis. Response: We have prepared a file containing the raw data used for Figure 3a (as well as Figures 1 and 2), which is provided as S2 Fig. A title for S2 Fig has been added in the Supporting Information. 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Response: We have corrected the reference list and confirmed that it is complete and accurate. Reviewer #1: This study provides valuable insights, but there are concerns regarding the results. The results section does not directly mention electroretinography (ERG) or histopathology in rd10 mice, but the discussion section does mention ERG and histopathology in rd10 mice. Based on the results of whole genome sequencing, etc., does this mean that all rd6-RD mice have the Pde6 rd10/rd10 mutation? Response: Thank you for your question. In this study, we did not perform analyses on rd10 mice; therefore, we do not have ERG or histopathological results for rd10 mice. In the Discussion, we referred to rd10 because we identified the rd10 mutation through whole-genome sequencing. The statement means that all rd6-RD mice have the Pde6 rd10/rd10 mutation. Reviewer #2: When working with spontaneously occurring animal models, it is essential to remain alert to the possibility of additional pathogenic mutations beyond those already reported. This manuscript underscores the previously unrecognized presence of the rd10 mutation in commercially available rd6 mice, delivering an important cautionary message to researchers who rely on this model. Both the experimental design and the overall presentation are clear and persuasive. My primary concern is that the conclusion—that severe retinal degeneration and retinal detachment in the rd6RD line arise from a combination of rd6 and rd10 mutations—is based solely on short-read whole-genome sequencing (WGS) data from a single mouse family. Because the Pde6b (c.1678C>T, p.R560C) mutation can be readily verified by Sanger sequencing, expanding the analysis to a larger cohort of animals would greatly strengthen the evidence. In addition, since rd10 mice are commercially available, crossing them with rd6 mice lacking the Pde6b mutation would test whether the rd6RD phenotype is truly reproducible, further enhancing the robustness of the conclusions. Response: Thank you for your question. We have prepared S3 Table to address the comment regarding expanding the analysis to a larger cohort of animals. As Supplementary Information, we have included a table summarizing the correlation between phenotype and genotype. While the original submission included 10 animals, we have added additional data to bring the total to 18 animals. Accordingly, we revised the last four sentences of the Results section and added the title for S3 Fig. in the Supporting Information. As you pointed out, since rd10 mice are commercially available, crossing them with rd6 mice lacking the Pde6b mutation would allow us to test whether the rd6RD phenotype is truly reproducible, thereby further strengthening the robustness of our conclusions. We would like to consider this in our future studies. Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0332446.r002
5 Aug 2025 Decision Letter - Tatsuya Inoue, Editor PONE-D-25-22608R1Identification of coexisting Mfrprd6 and Pde6brd10 mutations causing spontaneous retinal detachment in commercially available rd6 micePLOS ONE Dear Dr. Igarashi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Sep 19 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Tatsuya Inoue Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): In the present study, the authors demonstrated the phenotype-genotype correlation in the rd6-RD mice. The manuscript is well-written, however the authors should address my concerns before publication. It seems that the authors did not mention why the retinal detachment occurred in rd6-RD mice. It would be better to add the molecular biological consideration in the Discussion section. Is there any similarity in gene expression between Mfrp and Pde6b? [Note: HTML markup is below. Please do not edit.] 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 #2: All comments have been addressed ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #2: Yes ****** 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 #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 #2: (No Response) ****** 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 #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0332446.r003
Revision 2
15 Aug 2025 Author Response Journal Requirements: In the present study, the authors demonstrated the phenotype-genotype correlation in the rd6-RD mice. The manuscript is well-written, however the authors should address my concerns before publication. 1. It seems that the authors did not mention why the retinal detachment occurred in rd6-RD mice. It would be better to add the molecular biological consideration in the Discussion section. Response: We thank the reviewer for this valuable comment. We agree that a molecular biological consideration regarding the occurrence of retinal detachment in rd6-RD mice should be included. We have now expanded the Discussion section to address this point on Page 16 and 17. Previous studies have demonstrated that Mfrp deficiency impairs the development and maintenance of photoreceptor outer segments via RPE dysfunction [16] and causes RPE atrophy and consequent photoreceptor degeneration [17]. Moreover, recent biochemical analysis revealed that Mfrp functions as a molecular hub in the apical membrane of RPE cells, coordinating lipid homeostasis and protein trafficking [18]. Previous reviews have detailed the mechanisms underlying phototransduction failure and photoreceptor cell death in rd10 mice [20] and recent comparative studies have demonstrated that the rd10 mutation induces protein mislocalization and instability, leading to cGMP-mediated cell death [21]. In this study, rd6-RD mice were found to harbor both the Mfrp mutation, which is associated with impaired RPE function and defective photoreceptor outer segment phagocytosis, and the Pde6b mutation, which causes rapid photoreceptor degeneration due to impaired phototransduction. The combination of these genetic defects may lead to marked structural instability of the outer retina, disruption of the outer limiting membrane, and weakening of adhesion between the neural retina and the RPE. Moreover, accelerated photoreceptor cell death in rd6-RD mice could promote extracellular matrix remodeling and microglial activation, further compromising retinal integrity. These molecular and cellular alterations may act synergistically to facilitate the development of non-rhegmatogenous retinal detachment in this model. 2. Is there any similarity in gene expression between Mfrp and Pde6b? Response: We appreciate the reviewer’s question regarding potential similarities in the expression profiles of Mfrp and Pde6b. We added the Discussion section to address this point on Page 17. According to previous transcriptome analyses and public expression databases [22], both Mfrp and Pde6b exhibit retina-enriched expression, although they are predominantly localized to different retinal cell types. Mfrp is expressed mainly in the RPE and ciliary body [16], whereas Pde6b is expressed specifically in rod photoreceptors, where it plays an essential role in phototransduction [20]. Despite these differences in cell-type localization, transcriptome studies of retinal degenerative models have reported that loss-of-function mutations in either gene can lead to downstream dysregulation of common pathways, including photoreceptor survival, oxidative stress responses, and inflammation-related signaling [23, 24]. Therefore, while the upstream expression sites differ, there is overlap in the secondary gene expression changes observed in degenerating retina due to Mfrp or Pde6b dysfunction. Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.doc https://doi.org/10.1371/journal.pone.0332446.r004
31 Aug 2025 Decision Letter - Tatsuya Inoue, Editor Identification of coexisting Mfrprd6 and Pde6brd10 mutations causing spontaneous retinal detachment in commercially available rd6 mice PONE-D-25-22608R2 Dear Dr. Igarashi, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Tatsuya Inoue Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0332446.r005
Formally Accepted
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Identification of coexisting Mfrp^rd6 and Pde6b^rd10 mutations causing spontaneous retinal detachment in commercially available rd6 mice

Identification of coexisting Mfrp^rd6 and Pde6b^rd10 mutations causing spontaneous retinal detachment in commercially available rd6 mice

Peer Review History

Open letter on the publication of peer review reports