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Nature. 2019 Jul;571(7763):107-111. doi: 10.1038/s41586-019-1312-2. Epub 2019 Jun 19.

Noncoding deletions reveal a gene that is critical for intestinal function.

Author information

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. Doron.Lancet@weizmann.ac.il.
24
The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Yair.Anikster@sheba.health.gov.il.
25
Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel. Yair.Anikster@sheba.health.gov.il.
26
Wohl Institute for Translational Medicine, Sheba Medical Center, Ramat Gan, Israel. Yair.Anikster@sheba.health.gov.il.
27
Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. LAPennacchio@lbl.gov.
28
US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA. LAPennacchio@lbl.gov.
29
Comparative Biochemistry Program, University of California Berkeley, Berkeley, CA, USA. LAPennacchio@lbl.gov.

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.

PMID:
31217582
DOI:
10.1038/s41586-019-1312-2

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