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. Epub 2015 Mar 2.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins / metabolism
  • Child
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA-Directed RNA Polymerases / metabolism
  • De Lange Syndrome / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Male
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation, Missense
  • Repressor Proteins / genetics*
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / metabolism

Substances

  • AFF4 protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Multiprotein Complexes
  • Repressor Proteins
  • Transcriptional Elongation Factors
  • cohesins
  • DNA-Directed RNA Polymerases
  • RNA polymerase alpha subunit

Associated data

  • GEO/GSE64031
  • GEO/GSE64034
  • SRA/SRP050576