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DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect

C U Kirchgessner1, C K Patil, J W Evans

  • 1Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.

Science (New York, N.Y.)
|February 24, 1995
PubMed

Insights

Severe combined immunodeficient (SCID) mice lack B and T cell immunity due to a DNA repair defect. The catalytic subunit of DNA-dependent protein kinase, p350, is identified as the defective gene in SCID mice.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Severe combined immunodeficient (SCID) mice exhibit cellular hypersensitivity to ionizing radiation and lack B and T cell immunity.
  • SCID is characterized by a deficiency in a recombination process essential for DNA double-strand break repair and V(D)J recombination.

Purpose of the Study:

  • To identify the genetic defect responsible for the SCID phenotype in mice.
  • To investigate the role of the DNA-dependent protein kinase catalytic subunit (p350) in SCID.

Main Methods:

  • Genetic analysis and complementation studies were performed.
  • Chromosomal mapping was used to localize the SCID gene.
  • Protein expression levels were compared between SCID and wild-type mice.

Main Results:

  • The catalytic subunit of DNA-dependent protein kinase, p350, was identified as a strong candidate for the SCID gene.
  • The p350 gene and a gene complementing the SCID defect colocalize to human chromosome 8q11.
  • Chromosomal fragments expressing p350 complemented the SCID phenotype, and p350 protein levels were significantly reduced in SCID mouse cells.

Conclusions:

  • The p350 gene defect is responsible for the SCID phenotype in mice.
  • This finding provides a molecular basis for understanding SCID and potential therapeutic strategies.

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