Noncoding deletions reveal a gene that is critical for intestinal function

  • Nature. 2019 Jul;571(7763):107-111. doi: 10.1038/s41586-019-1312-2.
Danit Oz-Levi  1 ,  Tsviya Olender  1 ,  Ifat Bar-Joseph  2  3 ,  Yiwen Zhu  4 ,  Dina Marek-Yagel  2  3  5 ,  Iros Barozzi  4  6 ,  Marco Osterwalder  4 ,  Anna Alkelai  7 ,  Elizabeth K Ruzzo  8 ,  Yujun Han  9 ,  Erica S M Vos  10 ,  Haike Reznik-Wolf  2  3 ,  Corina Hartman  3  11 ,  Raanan Shamir  3  11 ,  Batia Weiss  3  5 ,  Rivka Shapiro  3  11 ,  Ben Pode-Shakked  3  5 ,  Pavlo Tatarskyy  1 ,  Roni Milgrom  1 ,  Michael Schvimer  12 ,  Iris Barshack  3  12 ,  Denise M Imai  13 ,  Devin Coleman-Derr  14 ,  Diane E Dickel  4 ,  Alex S Nord  4  15 ,  Veena Afzal  4 ,  Kelly Lammerts van Bueren  16 ,  Ralston M Barnes  16 ,  Brian L Black  16 ,  Christopher N Mayhew  17 ,  Matthew F Kuhar  17 ,  Amy Pitstick  17 ,  Mehmet Tekman  18 ,  Horia C Stanescu  18 ,  James M Wells  17  19  20 ,  Robert Kleta  18 ,  Wouter de Laat  10 ,  David B Goldstein  7 ,  Elon Pras  2  3 ,  Axel Visel  4  21  22 ,  Doron Lancet  23 ,  Yair Anikster  24  25  26 ,  Len A Pennacchio  27  28  29
Affiliations
  • 1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 2. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.
  • 3. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 4. Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • 5. Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
  • 6. Department of Surgery and Cancer, Imperial College London, London, UK.
  • 7. Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
  • 8. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
  • 9. Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA.
  • 10. Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
  • 11. Schneider Children's Medical Center, Petach Tikva, Israel.
  • 12. Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
  • 13. Comparative Pathology Laboratory, University of California Davis, Davis, CA, USA.
  • 14. Plant Gene Expression Center, USDA ARS, Albany, CA, USA.
  • 15. Center for Neuroscience, University of California Davis, Davis, CA, USA.
  • 16. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 17. Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 18. Centre for Nephrology, University College London, London, UK.
  • 19. Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 20. Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 21. School of Natural Sciences, University of California, Merced, CA, USA.
  • 22. US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
  • 23. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. [email protected].
  • 24. The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. [email protected].
  • 25. Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel. [email protected].
  • 26. Wohl Institute for Translational Medicine, Sheba Medical Center, Ramat Gan, Israel. [email protected].
  • 27. Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. [email protected].
  • 28. US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA. [email protected].
  • 29. Comparative Biochemistry Program, University of California Berkeley, Berkeley, CA, USA. [email protected].
PMID: 31217582 DOI: 10.1038/s41586-019-1312-2
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.