title: GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome.
abstract: Previous reports of GATA2 mutations have focused on the coding region of the gene or full gene deletions. We recently identified 2 patients with novel insertion/deletion mutations predicted to result in mRNA nonsense-mediated decay, suggesting haploinsufficiency as the mechanism of GATA2 deficient disease. We therefore screened patients without identified exonic lesions for mutations within conserved noncoding and intronic regions. We discovered 1 patient with an intronic deletion mutation, 4 patients with point mutations within a conserved intronic element, and 3 patients with reduced or absent transcription from 1 allele. All mutations affected GATA2 transcription. Full-length cDNA analysis provided evidence for decreased expression of the mutant alleles. The intronic deletion and point mutations considerably reduced the enhancer activity of the intron 5 enhancer. Analysis of 512 immune system genes revealed similar expression profiles in all clinically affected patients and reduced GATA2 transcript levels. These mutations strongly support the haploinsufficient nature of GATA2 deficiency and identify transcriptional mechanisms and targets that lead to MonoMAC syndrome.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Johnson
authors.forename: E Liana
authors.initials: EL
authors.lastname: Falcone
authors.forename: Rajendran
authors.initials: R
authors.lastname: Sanalkumar
authors.forename: Lauren
authors.initials: L
authors.lastname: Sanchez
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cuellar-Rodriguez
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Lemieux
authors.forename: Christa S
authors.initials: CS
authors.lastname: Zerbe
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence / Q000235:genetics; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D020014:K562 Cells; D007970:Leukopenia / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000473:pathology; D009154:Mutation / Q000502:physiology*; D015270:Mycobacterium avium-intracellulare Infection / Q000097:blood / Q000235:genetics*; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics; D013577:Syndrome; D055815:Young Adult
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human