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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
Summary
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.