Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.
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.
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.
Kosuke
K
Izumi
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Ryuichiro
R
Nakato
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Zhe
Z
Zhang
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Andrew C
AC
Edmondson
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Sarah
S
Noon
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Matthew C
MC
Dulik
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Ramakrishnan
R
Rajagopalan
National Human Genome Research Institute (NHGRI), US National Institutes of Health, Bethesda, Maryland, USA.
Charles P
CP
Venditti
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
Karen
0000000182001733
K
Gripp
Department of Pediatrics, Division of Genetics, Montefiore Medical Center, Bronx, New York, USA.
Joy
J
Samanich
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.
Elaine H
EH
Zackai
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.
Matthew A
MA
Deardorff
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Dinah
D
Clark
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.
Julian L
JL
Allen
Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
Dale
D
Dorsett
Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
Ziva
Z
Misulovin
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Makiko
M
Komata
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Masashige
M
Bando
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Maninder
M
Kaur
Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Yuki
Y
Katou
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.
Katsuhiko
K
Shirahige
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.
Ian D
ID
Krantz
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D003635:De Lange Syndrome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D012097:Repressor Proteins / Q000235:genetics*; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D012321:DNA-Directed RNA Polymerases; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D035602:Transcriptional Elongation Factors; D000097722:Cohesins; C471348:AFF4 protein, human; C113275:RNA polymerase alpha subunit