A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy

Keisuke Jimbo; Toshiaki Okuno; Ryuichi Ohgaki; Kou Nishikubo; Yuri Kitamura; Yumiko Sakurai; Lili Quan; Hiromichi Shoji; Yoshikatsu Kanai; Toshiaki Shimizu; Takehiko Yokomizo

doi:10.1371/journal.pone.0241869

Peer Review History

Original SubmissionAugust 14, 2020
22 Sep 2020 Decision Letter - Sylvie Mazoyer, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-20-25461 A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy PLOS ONE Dear Dr. Okuno, 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 Nov 06 2020 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. 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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: Jimbo et al. reported a sibling case with chronic enteropathy associated with SLCO2A1 gene (CEAS) and found a new missense variant (c.1688T>C) in the SLCO2A1 gene. They also confirmed that this mutation causes loss of transporter function by the PGE2 uptake experiment. Major point 1. Clinical features about the patients are unclear. For example, there is no description of patient III-1 and the location of the small intestinal lesions of patient III-3 is unclear. They should describe in detail the gastrointestinal and extraintestinal features of the patients. If possible, they should discuss the difference between siblings. Minor point 1. P6L74. The authors wrote, "the disease can now be genetically diagnosed...". but CEAS is diagnosed by clinical features and a genetic test and genetic test just help in diagnosing. Please revise this sentence. 2. P6L81. The word "consanguineous" should be wrong. Please make sure. 3. P9L120. The word "CNSU" should be changed to CEAS. 4. P10L150. There is no explanation about the representation of the black circle and so on in the Fig 3c. Reviewer #2: This is a new case report for the sibling of CEAS with compound heterozygous variants (c.940+1G>A and c.1688T>C). Jibo et al found a novel SLCO2A1 mutation (c.1688T>C) and confirmed that the SLCO2A1 variant (L563P) had no PGE2 transport activity when it was expressed in Flp-In T-Rex 293 cells. The structure model of SLCO2A1 suggests the substitution of Leu with Pro impairs the transport function. This paper is well-described, and molecular mechanism supports their clinical observation. Information on clinically associated mutations of SLCO2A1 is worthwhile to be shared for efficient genetical diagnosis. The following minor concerns are raised. 1. Figure 2A shows the metabolic pathway of both PGE2 and PGF2a; however, they are basically the same. They should combine them and show only essential parts of the pathway. 2. SLCO2A1 defects also cause PHO/PDP. Have the authors observed any clinical features of PHO/PDP in these patients? It would be appreciated to describe or mention clinical manifestations of PHO/PDP. 3. In Figure 4, the authors suggest that L563 side chain is not directly involved in substrate biding because the side chain is outward (line 168). Does this mean that the side of the leucine outward from the helix does not affect substrate binding? This description is a little bit hard to understand. It would be nicer If the authors clarified this molecular basis more clearly. ****** 6. 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Revision 1
14 Oct 2020 Author Response Point-by-point Responses Reviewer #1: Jimbo et al. reported a sibling case with chronic enteropathy associated with SLCO2A1 gene (CEAS) and found a new missense variant (c.1688T>C) in the SLCO2A1 gene. They also confirmed that this mutation causes loss of transporter function by the PGE2 uptake experiment. Major point 1. Clinical features about the patients are unclear. For example, there is no description of patient III-1 and the location of the small intestinal lesions of patient III-3 is unclear. They should describe in detail the gastrointestinal and extraintestinal features of the patients. If possible, they should discuss the difference between siblings. Response: Thank you very much for your critical comments. We described clinical features about the patients as follows: P6L86: However, we observed multiple circular and tape-like shallow ulcers in the entire small intestine and predominantly in the lower ileum using intestinal capsule endoscopy, strongly indicating CEAS (Fig. 1B). P7L98: Through genetic analysis of the parents and siblings, we identified the same heterozygous variants in the SLCO2A1 gene of patient III-1, who had past medical history of recurrent abdominal pain, but it had not been scrutinized at medical institutes. After the identification of the genetic mutation, she was found to have hypoproteinemia and anemia similar to patient III-3 by laboratory test. She also exhibited multiple shallow and tape-like ulcers in entire small intestine and predominantly in the lower ileum by capsule endoscopy (Fig. 1B). Minor point 1. P6L74. The authors wrote, "the disease can now be genetically diagnosed...". but CEAS is diagnosed by clinical features and a genetic test and genetic test just help in diagnosing. Please revise this sentence. Response: Thank you for your critical comment. We revised our manuscript as follow. P6L74: the disease is diagnosed by clinical features and a genetic test in the SLCO2A1 gene. 2. P6L81. The word "consanguineous" should be wrong. Please make sure. Response: Thank you for your useful comment. We modified our manuscript as follow. P6L81: to healthy non-consanguineous parents (Fig. 1A). 3. P9L120. The word "CNSU" should be changed to CEAS. Response: Thank you for your useful comment. We modified our manuscript as follow. P9L127: in the CEAS patients were significantly higher 4. P10L150. There is no explanation about the representation of the black circle and so on in the Fig 3c. Response: Thank you for your useful comment. We added the representations of the black circle, open circle, and open triangle in the Fig 3c. We thank Reviewer #1 for the constructive and insightful comments, which helped us to substantially improve our manuscript. Reviewer #2: This is a new case report for the sibling of CEAS with compound heterozygous variants (c.940+1G>A and c.1688T>C). Jibo et al found a novel SLCO2A1 mutation (c.1688T>C) and confirmed that the SLCO2A1 variant (L563P) had no PGE2 transport activity when it was expressed in Flp-In T-Rex 293 cells. The structure model of SLCO2A1 suggests the substitution of Leu with Pro impairs the transport function. This paper is well-described, and molecular mechanism supports their clinical observation. Information on clinically associated mutations of SLCO2A1 is worthwhile to be shared for efficient genetical diagnosis. The following minor concerns are raised. 1. Figure 2A shows the metabolic pathway of both PGE2 and PGF2a; however, they are basically the same. They should combine them and show only essential parts of the pathway. Response: Thank you for useful comments. We have combined the metabolic pathway of PGE2 and PGF2a in Figure 2A. 2. SLCO2A1 defects also cause PHO/PDP. Have the authors observed any clinical features of PHO/PDP in these patients? It would be appreciated to describe or mention clinical manifestations of PHO/PDP. Response: Thank you for critical comments. We consulted two CEAS patients to a dermatologist in our hospital and got the answer that there were no characteristic findings of PHO/PDP. Therefore, we modified our manuscript as follows. P7L104: (Fig. 1B). In addition, because SLCO2A1 defects also cause another disease primary hypertrophic osteoarthropathy (PHO)/pachydermoperiostosis (PDP), we consulted two CEAS patients to a dermatologist in our hospital and got the answer that there were no characteristic findings of PHO/PDP. 3. In Figure 4, the authors suggest that L563 side chain is not directly involved in substrate biding because the side chain is outward (line 168). Does this mean that the side of the leucine outward from the helix does not affect substrate binding? This description is a little bit hard to understand. It would be nicer If the authors clarified this molecular basis more clearly. Response: Thank you for useful comments. We consider that the side chain of the leucine outward from the helix is not involved in substrate binding. We modified the manuscript as follows: P12L172: The substrate may occupy a pocket between the transmembrane helixes similar to that of GlpT. We thank Reviewer #2 for the constructive and insightful comments, which have helped us to substantially improve our manuscript. Attachments Attachment Submitted filename: Response_to_ Reviewers.docx https://doi.org/10.1371/journal.pone.0241869.r002
22 Oct 2020 Decision Letter - Sylvie Mazoyer, Editor A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy PONE-D-20-25461R1 Dear Dr. Okuno, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Sylvie Mazoyer, 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 #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: Additional information about clinical features in these CEAS patients is highly appreciated and useful. ****** 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: Yes:** Takeo Nakanishi https://doi.org/10.1371/journal.pone.0241869.r003
Formally Accepted
29 Oct 2020 Acceptance Letter - Sylvie Mazoyer, Editor PONE-D-20-25461R1 A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy Dear Dr. Okuno: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr Sylvie Mazoyer Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241869.r004

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