title: Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome.
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.
  
  
  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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Klein
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Ghahremani
authors.forename: Pamela
authors.initials: P
authors.lastname: Kempert
authors.forename: Mariam
authors.initials: M
authors.lastname: Ischander
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
mesh_terms: D000595:Amino Acid Sequence; D003560:Cysts / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008171:Lung Diseases / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases