Noncoding deletions reveal a gene that is critical for intestinal function

Danit Oz-Levi, Tsviya Olender, Ifat Bar-Joseph, Yiwen Zhu, Dina Marek-Yagel, Iros Barozzi, Marco Osterwalder, Anna Alkelai, Elizabeth K. Ruzzo, Yujun Han, Erica S. M. Vos, Haike Reznik-Wolf, Corina Hartman, Raanan Shamir, Batia Weiss, Rivka Shapiro, Ben Pode-Shakked, Pavlo Tatarskyy, Roni Milgrom, Michael Schvimer, Iris Barshack, Denise M. Imai, Devin Coleman-Derr, Diane E. Dickel, Alex S. Nord, Veena Afzal, Kelly Lammerts Bueren, Ralston M. Barnes, Brian L. Black, Christopher N. Mayhew, Matthew F. Kuhar, Amy Pitstick, Mehmet Tekman, Horia C. Stanescu, James M. Wells, Robert Kleta, Wouter Laat, David B. Goldstein, Elon Pras, Axel Visel, Doron Lancet (), Yair Anikster () and Len A. Pennacchio ()
Additional contact information
Danit Oz-Levi: Weizmann Institute of Science
Tsviya Olender: Weizmann Institute of Science
Ifat Bar-Joseph: Sheba Medical Center
Yiwen Zhu: Lawrence Berkeley National Laboratory
Dina Marek-Yagel: Sheba Medical Center
Iros Barozzi: Lawrence Berkeley National Laboratory
Marco Osterwalder: Lawrence Berkeley National Laboratory
Anna Alkelai: Columbia University Medical Center
Elizabeth K. Ruzzo: University of California Los Angeles
Yujun Han: Duke University School of Medicine
Erica S. M. Vos: Hubrecht Institute-KNAW and University Medical Center Utrecht
Haike Reznik-Wolf: Sheba Medical Center
Corina Hartman: Tel Aviv University
Raanan Shamir: Tel Aviv University
Batia Weiss: Tel Aviv University
Rivka Shapiro: Tel Aviv University
Ben Pode-Shakked: Tel Aviv University
Pavlo Tatarskyy: Weizmann Institute of Science
Roni Milgrom: Weizmann Institute of Science
Michael Schvimer: Sheba Medical Center
Iris Barshack: Tel Aviv University
Denise M. Imai: University of California Davis
Devin Coleman-Derr: Plant Gene Expression Center, USDA ARS
Diane E. Dickel: Lawrence Berkeley National Laboratory
Alex S. Nord: Lawrence Berkeley National Laboratory
Veena Afzal: Lawrence Berkeley National Laboratory
Kelly Lammerts Bueren: University of California San Francisco
Ralston M. Barnes: University of California San Francisco
Brian L. Black: University of California San Francisco
Christopher N. Mayhew: Cincinnati Children’s Hospital Medical Center
Matthew F. Kuhar: Cincinnati Children’s Hospital Medical Center
Amy Pitstick: Cincinnati Children’s Hospital Medical Center
Mehmet Tekman: University College London
Horia C. Stanescu: University College London
James M. Wells: Cincinnati Children’s Hospital Medical Center
Robert Kleta: University College London
Wouter Laat: Hubrecht Institute-KNAW and University Medical Center Utrecht
David B. Goldstein: Columbia University Medical Center
Elon Pras: Sheba Medical Center
Axel Visel: Lawrence Berkeley National Laboratory
Doron Lancet: Weizmann Institute of Science
Yair Anikster: Tel Aviv University
Len A. Pennacchio: Lawrence Berkeley National Laboratory

Nature, 2019, vol. 571, issue 7763, 107-111

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1312-2

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