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Severe Fanconi Anemia phenotypes in Fancd2 depletion mice

Qiao Yang1, Hui Xie2, Yixinhe Zhong1

  • 1Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China.

Biochemical and Biophysical Research Communications
|May 13, 2019
PubMed

Insights

A new Fanconi anemia (FA) mouse model with a Fancd2 knockout exhibits more severe symptoms, including anemia, offering insights into FA pathogenesis and bone marrow failure. This model aids in understanding FA patient conditions.

Area of Science:

  • Genetics
  • Molecular Biology
  • Hematology

Background:

  • Fanconi anemia (FA) is a genetic disorder causing bone marrow failure and DNA damage hypersensitivity.
  • The FANCD2 protein is crucial for the FA pathway.
  • Existing mouse models have limitations in fully recapitulating FA phenotypes.

Purpose of the Study:

  • To generate and characterize a novel Fancd2 knockout mouse model using CRISPR-Cas9.
  • To investigate the in vivo role of FANCD2 in FA pathogenesis.
  • To create a more accurate model for studying FA-related bone marrow failure.

Main Methods:

  • CRISPR-Cas9 gene editing was used to create a 7bp deletion in the Fancd2 gene 5' terminus.
  • A congenic C57BL/6J background was utilized for the mouse strain.
  • Phenotypic characterization included assessing lethality, developmental abnormalities, hypogonadism, and hematopoiesis.

Main Results:

  • The Fancd2 knockout mice (Fancd2-/-) showed more severe manifestations than previous models, including increased embryonic/postnatal lethality and microphthalmia.
  • A novel anemia phenotype was observed in Fancd2-/- mice.
  • Hematopoietic stem and progenitor cells exhibited increased apoptosis, G2/M arrest, and hypersensitivity to DNA damaging agents (MMC, IR).

Conclusions:

  • The generated Fancd2-/- mice closely resemble FA patient symptoms, particularly pancytopenia and bone marrow failure.
  • This new mouse model is a valuable tool for understanding FA pathogenesis.
  • Further research with this model can elucidate mechanisms of bone marrow failure in FA.
Keywords:
Crispr-Cas9FANCD2Fanconi anemiaMouse model

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