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J Med Genet 51:294-302 doi:10.1136/jmedgenet-2013-101943
  • Cancer genetics
  • Original article

Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome

  1. Julian A Martinez-Agosto1,7,8
  1. 1Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  2. 2Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  3. 3Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  4. 4Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  5. 5Division of Pulmonary Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  6. 6Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California, USA
  7. 7Jonsson Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  8. 8Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  1. Correspondence to Dr Julian A Martinez-Agosto, 695 Charles E. Young Drive South, Gonda Research Center Room 4554, Los Angeles, CA 90095, USA; julianmartinez{at}mednet.ucla.edu
  • Received 10 October 2013
  • Revised 6 February 2014
  • Accepted 21 February 2014
  • Published Online First 27 March 2014

Abstract

Background Constitutional DICER1 mutations have been associated with pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig tumours and multinodular goitres, while somatic DICER1 mutations have been reported in additional tumour types. Here we report a novel syndrome termed GLOW, an acronym for its core phenotypic findings, which include Global developmental delay, Lung cysts, Overgrowth and Wilms tumour caused by mutations in the RNase IIIb domain of DICER1.

Methods and results We performed whole exome sequencing on peripheral mononuclear blood cells of an affected proband and identified a de novo missense mutation in the RNase IIIb domain of DICER1. We confirmed an additional de novo missense mutation in the same domain of an unrelated case by Sanger sequencing. These missense mutations in the RNase IIIb domain of DICER1 are suspected to affect one of four metal binding sites located within this domain. Pyrosequencing was used to determine the relative abundance of mutant alleles in various tissue types. The relative mutation abundance is highest in Wilms tumour and unaffected kidney samples when compared with blood, confirming that the mutation is mosaic. Finally, we performed bioinformatic analysis of microRNAs expressed in murine cells carrying specific Dicer1 RNase IIIb domain metal binding site-associated mutations. We have identified a subset of 3p microRNAs that are overexpressed whose target genes are over-represented in mTOR, MAPK and TGF-β signalling pathways.

Conclusions We propose that mutations affecting the metal binding sites of the DICER1 RNase IIIb domain alter the balance of 3p and 5p microRNAs leading to deregulation of these growth signalling pathways, causing a novel human overgrowth syndrome.