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Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

  1. Author:
    Brodie,Seth
    Khincha, Payal P.
    Giri, Neelam
    Bouk,Aaron
    Steinberg,Mia
    Dai,Jieqiong
    Jessop, Lea
    Donovan, Frank X.
    Chandrasekharappa, Settara C.
    de Andrade, Kelvin C.
    Maric, Irina
    Ellis, Steven R.
    Mirabello, Lisa
    Alter, Blanche P.
    Savage, Sharon A.

  2. Author Address

    Frederick Natl Lab Canc Res, Canc Genom Res Lab, Leidos Biomed Res, Frederick, MD 20850 USA.NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.NCI, Lab Genet Susceptibil, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA.NIH, Dept Lab Med, Clin Ctr, Bethesda, MD 20892 USA.Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA.
    1. Year: 2021
    2. Date: AUG
  2. Journal: COLD SPRING HARBOR MOLECULAR CASE STUDIES
  3. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT,
    1. 7
    2. 4
  5. Type of Article: Article
  6. Article Number: a006015
  7. ISSN: 2373-2873
  1. Abstract:

    IKZF1 encodes Ikaros, a zinc finger-containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C> T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C> T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.

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External Sources

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  2. DOI: 10.1101/mcs.a006015
  3. View record in Web of Science®
  4. WOS: 000681087900006

Library Notes

  1. Fiscal Year: FY2020-2021
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