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

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.

SUBMITTER: Izumi K

PROVIDER: S-EPMC4380798 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Izumi Kosuke K Nakato Ryuichiro R Zhang Zhe Z Edmondson Andrew C AC Noon Sarah S Dulik Matthew C MC Rajagopalan Ramakrishnan R Venditti Charles P CP Gripp Karen K Samanich Joy J Zackai Elaine H EH Deardorff Matthew A MA Clark Dinah D Allen Julian L JL Dorsett Dale D Misulovin Ziva Z Komata Makiko M Bando Masashige M Kaur Maninder M Katou Yuki Y Shirahige Katsuhiko K Krantz Ian D ID

Nature genetics 20150302 4

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 defec ...[more]

PMID: 25730767

Dataset Information

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

Publications

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

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