@article{cbaf2a9c794044b6a5931227fa4e1cdd,
title = "Noncoding deletions reveal a gene that is critical for intestinal function",
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.",
keywords = "Animals, Chromosomes, Human, Pair 16/genetics, Diarrhea/congenital, Disease Models, Animal, Enhancer Elements, Genetic/genetics, Female, Gene Expression Regulation, Developmental, Genes, Genes, Reporter, Genetic Loci/genetics, Humans, Intestines/physiology, Male, Mice, Mice, Knockout, Mice, Transgenic, Pedigree, Phenotype, Sequence Deletion/genetics, Transcriptional Activation, Transcriptome/genetics, Transgenes/genetics",
author = "Danit Oz-Levi and Tsviya Olender and Ifat Bar-Joseph and Yiwen Zhu and Dina Marek-Yagel and Iros Barozzi and Marco Osterwalder and Anna Alkelai and Ruzzo, {Elizabeth K} and Yujun Han and Vos, {Erica S M} and Haike Reznik-Wolf and Corina Hartman and Raanan Shamir and Batia Weiss and Rivka Shapiro and Ben Pode-Shakked and Pavlo Tatarskyy and Roni Milgrom and Michael Schvimer and Iris Barshack and Imai, {Denise M} and Devin Coleman-Derr and Dickel, {Diane E} and Nord, {Alex S} and Veena Afzal and {van Bueren}, {Kelly Lammerts} and Barnes, {Ralston M} and Black, {Brian L} and Mayhew, {Christopher N} and Kuhar, {Matthew F} and Amy Pitstick and Mehmet Tekman and Stanescu, {Horia C} and Wells, {James M} and Robert Kleta and {de Laat}, Wouter and Goldstein, {David B} and Elon Pras and Axel Visel and Doron Lancet and Yair Anikster and Pennacchio, {Len A}",
year = "2019",
month = jul,
doi = "10.1038/s41586-019-1312-2",
language = "English",
volume = "571",
pages = "107--111",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7763",
}