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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 M; Coleman-Derr, Devin; Dickel, Diane E; Nord, Alex S; 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.
Afiliación
  • 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.
  • Zhu Y; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Marek-Yagel D; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Barozzi I; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.
  • Osterwalder M; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Alkelai A; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
  • Ruzzo EK; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Han Y; Department of Surgery and Cancer, Imperial College London, London, UK.
  • Vos ESM; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Reznik-Wolf H; Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
  • Hartman C; Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
  • Shamir R; Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA.
  • Weiss B; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
  • Shapiro R; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.
  • Pode-Shakked B; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Tatarskyy P; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Milgrom R; Schneider Children's Medical Center, Petach Tikva, Israel.
  • Schvimer M; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Barshack I; Schneider Children's Medical Center, Petach Tikva, Israel.
  • Imai DM; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Coleman-Derr D; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
  • Dickel DE; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Nord AS; Schneider Children's Medical Center, Petach Tikva, Israel.
  • Afzal V; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • van Bueren KL; Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
  • Barnes RM; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • Black BL; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • Mayhew CN; Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
  • Kuhar MF; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Pitstick A; Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
  • Tekman M; Comparative Pathology Laboratory, University of California Davis, Davis, CA, USA.
  • Stanescu HC; Plant Gene Expression Center, USDA ARS, Albany, CA, USA.
  • Wells JM; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Kleta R; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • de Laat W; Center for Neuroscience, University of California Davis, Davis, CA, USA.
  • Goldstein DB; Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Pras E; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • Visel A; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • Lancet D; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • Anikster Y; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Pennacchio LA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nature ; 571(7763): 107-111, 2019 07.
Article en En | MEDLINE | ID: mdl-31217582
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Elementos de Facilitación Genéticos / Eliminación de Secuencia / Regulación del Desarrollo de la Expresión Génica / Diarrea / Genes / Intestinos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Elementos de Facilitación Genéticos / Eliminación de Secuencia / Regulación del Desarrollo de la Expresión Génica / Diarrea / Genes / Intestinos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido