2. Academic Validation
  3. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

  • Nat Genet. 2015 Apr;47(4):338-44. doi: 10.1038/ng.3229.
Kosuke Izumi 1,  Ryuichiro Nakato 2,  Zhe Zhang 3,  Andrew C Edmondson 4,  Sarah Noon 4,  Matthew C Dulik 5,  Ramakrishnan Rajagopalan 5,  Charles P Venditti 6,  Karen Gripp 7,  Joy Samanich 8,  Elaine H Zackai 9,  Matthew A Deardorff 9,  Dinah Clark 4,  Julian L Allen 10,  Dale Dorsett 11,  Ziva Misulovin 11,  Makiko Komata 2,  Masashige Bando 2,  Maninder Kaur 4,  Yuki Katou 2,  Katsuhiko Shirahige 12,  Ian D Krantz 9
Affiliations

Affiliations

  • 1 1] Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
  • 2 Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
  • 3 Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 4 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 5 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 6 National Human Genome Research Institute (NHGRI), US National Institutes of Health, Bethesda, Maryland, USA.
  • 7 Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
  • 8 Department of Pediatrics, Division of Genetics, Montefiore Medical Center, Bronx, New York, USA.
  • 9 1] Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. [2] The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 10 1] The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2] Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 11 Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
  • 12 1] Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan. [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Japan.
PMID: 25730767 DOI: 10.1038/ng.3229
Abstract

Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

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