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

Autor: Oz-Levi D; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Olender T; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Bar-Joseph I; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Zhu Y; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Marek-Yagel D; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel., Barozzi I; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Department of Surgery and Cancer, Imperial College London, London, UK., Osterwalder M; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Alkelai A; Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA., Ruzzo EK; Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA., Han Y; Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA., Vos ESM; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands., Reznik-Wolf H; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Hartman C; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Schneider Children's Medical Center, Petach Tikva, Israel., Shamir R; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Schneider Children's Medical Center, Petach Tikva, Israel., Weiss B; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel., Shapiro R; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Schneider Children's Medical Center, Petach Tikva, Israel., Pode-Shakked B; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel., Tatarskyy P; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Milgrom R; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Schvimer M; Department of Pathology, Sheba Medical Center, Ramat Gan, Israel., Barshack I; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Pathology, Sheba Medical Center, Ramat Gan, Israel., Imai DM; Comparative Pathology Laboratory, University of California Davis, Davis, CA, USA., Coleman-Derr D; Plant Gene Expression Center, USDA ARS, Albany, CA, USA., Dickel DE; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Nord AS; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Center for Neuroscience, University of California Davis, Davis, CA, USA., Afzal V; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., van Bueren KL; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Barnes RM; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Black BL; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA., Mayhew CN; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Kuhar MF; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Pitstick A; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Tekman M; Centre for Nephrology, University College London, London, UK., Stanescu HC; Centre for Nephrology, University College London, London, UK., Wells JM; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Kleta R; Centre for Nephrology, University College London, London, UK., de Laat W; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands., Goldstein DB; Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA., Pras E; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Visel A; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; School of Natural Sciences, University of California, Merced, CA, USA.; US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA., Lancet D; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. Doron.Lancet@weizmann.ac.il., Anikster Y; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Yair.Anikster@sheba.health.gov.il.; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel. Yair.Anikster@sheba.health.gov.il.; Wohl Institute for Translational Medicine, Sheba Medical Center, Ramat Gan, Israel. Yair.Anikster@sheba.health.gov.il., Pennacchio LA; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. LAPennacchio@lbl.gov.; US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA. LAPennacchio@lbl.gov.; Comparative Biochemistry Program, University of California Berkeley, Berkeley, CA, USA. LAPennacchio@lbl.gov.
Jazyk: angličtina
Zdroj: Nature [Nature] 2019 Jul; Vol. 571 (7763), pp. 107-111. Date of Electronic Publication: 2019 Jun 19.
DOI: 10.1038/s41586-019-1312-2
Abstrakt: 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 infants 1,2 . 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.
Databáze: MEDLINE
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