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Title: Noncoding deletions reveal a gene that is critical for intestinal function

Abstract

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Authors:
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Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1594926
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 571; Journal Issue: 7763; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English

Citation Formats

Oz-Levi, Danit, Olender, Tsviya, Bar-Joseph, Ifat, Zhu, Yiwen, Marek-Yagel, Dina, Barozzi, Iros, Osterwalder, Marco, Alkelai, Anna, Ruzzo, Elizabeth K., Han, Yujun, Vos, Erica S. M., Reznik-Wolf, Haike, Hartman, Corina, Shamir, Raanan, Weiss, Batia, Shapiro, Rivka, Pode-Shakked, Ben, Tatarskyy, Pavlo, Milgrom, Roni, Schvimer, Michael, Barshack, Iris, Imai, Denise M., Coleman-Derr, Devin, Dickel, Diane E., Nord, Alex S., Afzal, Veena, van Bueren, Kelly Lammerts, Barnes, Ralston M., Black, Brian L., Mayhew, Christopher N., Kuhar, Matthew F., Pitstick, Amy, Tekman, Mehmet, Stanescu, Horia C., Wells, James M., Kleta, Robert, de Laat, Wouter, Goldstein, David B., Pras, Elon, Visel, Axel, Lancet, Doron, Anikster, Yair, and Pennacchio, Len A. Noncoding deletions reveal a gene that is critical for intestinal function. United States: N. p., 2019. Web. doi:10.1038/s41586-019-1312-2.
Oz-Levi, Danit, Olender, Tsviya, Bar-Joseph, Ifat, Zhu, Yiwen, Marek-Yagel, Dina, Barozzi, Iros, Osterwalder, Marco, Alkelai, Anna, Ruzzo, Elizabeth K., Han, Yujun, Vos, Erica S. M., Reznik-Wolf, Haike, Hartman, Corina, Shamir, Raanan, Weiss, Batia, Shapiro, Rivka, Pode-Shakked, Ben, Tatarskyy, Pavlo, Milgrom, Roni, Schvimer, Michael, Barshack, Iris, Imai, Denise M., Coleman-Derr, Devin, Dickel, Diane E., Nord, Alex S., Afzal, Veena, van Bueren, Kelly Lammerts, Barnes, Ralston M., Black, Brian L., Mayhew, Christopher N., Kuhar, Matthew F., Pitstick, Amy, Tekman, Mehmet, Stanescu, Horia C., Wells, James M., Kleta, Robert, de Laat, Wouter, Goldstein, David B., Pras, Elon, Visel, Axel, Lancet, Doron, Anikster, Yair, & Pennacchio, Len A. Noncoding deletions reveal a gene that is critical for intestinal function. United States. doi:10.1038/s41586-019-1312-2.
Oz-Levi, Danit, Olender, Tsviya, Bar-Joseph, Ifat, Zhu, Yiwen, Marek-Yagel, Dina, Barozzi, Iros, Osterwalder, Marco, Alkelai, Anna, Ruzzo, Elizabeth K., Han, Yujun, Vos, Erica S. M., Reznik-Wolf, Haike, Hartman, Corina, Shamir, Raanan, Weiss, Batia, Shapiro, Rivka, Pode-Shakked, Ben, Tatarskyy, Pavlo, Milgrom, Roni, Schvimer, Michael, Barshack, Iris, Imai, Denise M., Coleman-Derr, Devin, Dickel, Diane E., Nord, Alex S., Afzal, Veena, van Bueren, Kelly Lammerts, Barnes, Ralston M., Black, Brian L., Mayhew, Christopher N., Kuhar, Matthew F., Pitstick, Amy, Tekman, Mehmet, Stanescu, Horia C., Wells, James M., Kleta, Robert, de Laat, Wouter, Goldstein, David B., Pras, Elon, Visel, Axel, Lancet, Doron, Anikster, Yair, and Pennacchio, Len A. Wed . "Noncoding deletions reveal a gene that is critical for intestinal function". United States. doi:10.1038/s41586-019-1312-2.
@article{osti_1594926,
title = {Noncoding deletions reveal a gene that is critical for intestinal function},
author = {Oz-Levi, Danit and Olender, Tsviya and Bar-Joseph, Ifat and Zhu, Yiwen and Marek-Yagel, Dina and Barozzi, Iros and Osterwalder, Marco and Alkelai, Anna and Ruzzo, Elizabeth K. and Han, Yujun and Vos, Erica S. M. and Reznik-Wolf, Haike and Hartman, Corina and Shamir, Raanan and Weiss, Batia and Shapiro, Rivka and Pode-Shakked, Ben and Tatarskyy, Pavlo and Milgrom, Roni and Schvimer, Michael and Barshack, Iris and Imai, Denise M. and Coleman-Derr, Devin and Dickel, Diane E. and Nord, Alex S. and Afzal, Veena and van Bueren, Kelly Lammerts and Barnes, Ralston M. and Black, Brian L. and Mayhew, Christopher N. and Kuhar, Matthew F. and Pitstick, Amy and Tekman, Mehmet and Stanescu, Horia C. and Wells, James M. and Kleta, Robert and de Laat, Wouter and Goldstein, David B. and Pras, Elon and Visel, Axel and Lancet, Doron and Anikster, Yair and Pennacchio, Len A.},
abstractNote = {Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.},
doi = {10.1038/s41586-019-1312-2},
journal = {Nature (London)},
number = 7763,
volume = 571,
place = {United States},
year = {2019},
month = {6}
}

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