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 & 23 others Iris Barshack, Denise Imai, Devin Coleman-Derr, Diane E. Dickel, Alexander Nord, Veena Afzal, Kelly Lammerts van 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 de Laat, David B. Goldstein, Elon Pras, Axel Visel, Doron Lancet, Yair Anikster, Len A. Pennacchio

Research output: Contribution to journalLetter

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.

Original languageEnglish (US)
Pages (from-to)107-111
Number of pages5
JournalNature
Volume571
Issue number7763
DOIs
StatePublished - Jul 4 2019

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Intestines
Genes
Phenotype
Chromosomes, Human, Pair 16
Mutation
Sequence Deletion
Human Chromosomes
Gene Expression Profiling
Transgenes
Knockout Mice
Transgenic Mice
Open Reading Frames
Diarrhea
Genome
Gene Expression
Proteins

ASJC Scopus subject areas

  • General

Cite this

Oz-Levi, D., Olender, T., Bar-Joseph, I., Zhu, Y., Marek-Yagel, D., Barozzi, I., ... Pennacchio, L. A. (2019). Noncoding deletions reveal a gene that is critical for intestinal function. Nature, 571(7763), 107-111. https://doi.org/10.1038/s41586-019-1312-2

Noncoding deletions reveal a gene that is critical for intestinal function. / 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; Coleman-Derr, Devin; Dickel, Diane E.; Nord, Alexander; 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.

In: Nature, Vol. 571, No. 7763, 04.07.2019, p. 107-111.

Research output: Contribution to journalLetter

Oz-Levi, D, Olender, T, Bar-Joseph, I, Zhu, Y, Marek-Yagel, D, Barozzi, I, Osterwalder, M, Alkelai, A, Ruzzo, EK, Han, Y, Vos, ESM, Reznik-Wolf, H, Hartman, C, Shamir, R, Weiss, B, Shapiro, R, Pode-Shakked, B, Tatarskyy, P, Milgrom, R, Schvimer, M, Barshack, I, Imai, D, Coleman-Derr, D, Dickel, DE, Nord, A, Afzal, V, van Bueren, KL, Barnes, RM, Black, BL, Mayhew, CN, Kuhar, MF, Pitstick, A, Tekman, M, Stanescu, HC, Wells, JM, Kleta, R, de Laat, W, Goldstein, DB, Pras, E, Visel, A, Lancet, D, Anikster, Y & Pennacchio, LA 2019, 'Noncoding deletions reveal a gene that is critical for intestinal function', Nature, vol. 571, no. 7763, pp. 107-111. https://doi.org/10.1038/s41586-019-1312-2
Oz-Levi D, Olender T, Bar-Joseph I, Zhu Y, Marek-Yagel D, Barozzi I et al. Noncoding deletions reveal a gene that is critical for intestinal function. Nature. 2019 Jul 4;571(7763):107-111. https://doi.org/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 ; Coleman-Derr, Devin ; Dickel, Diane E. ; Nord, Alexander ; 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. In: Nature. 2019 ; Vol. 571, No. 7763. pp. 107-111.
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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.",
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AU - Olender, Tsviya

AU - Bar-Joseph, Ifat

AU - Zhu, Yiwen

AU - Marek-Yagel, Dina

AU - Barozzi, Iros

AU - Osterwalder, Marco

AU - Alkelai, Anna

AU - Ruzzo, Elizabeth K.

AU - Han, Yujun

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AU - Shamir, Raanan

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AU - Shapiro, Rivka

AU - Pode-Shakked, Ben

AU - Tatarskyy, Pavlo

AU - Milgrom, Roni

AU - Schvimer, Michael

AU - Barshack, Iris

AU - Imai, Denise

AU - Coleman-Derr, Devin

AU - Dickel, Diane E.

AU - Nord, Alexander

AU - Afzal, Veena

AU - van Bueren, Kelly Lammerts

AU - Barnes, Ralston M.

AU - Black, Brian L.

AU - Mayhew, Christopher N.

AU - Kuhar, Matthew F.

AU - Pitstick, Amy

AU - Tekman, Mehmet

AU - Stanescu, Horia C.

AU - Wells, James M.

AU - Kleta, Robert

AU - de Laat, Wouter

AU - Goldstein, David B.

AU - Pras, Elon

AU - Visel, Axel

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AU - Anikster, Yair

AU - Pennacchio, Len A.

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