title: Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice.
abstract: The severe combined immune deficiency (SCID) mouse was reported as an animal model for human immune deficiency. Through the course of several studies, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) gene came to be considered a candidate for the SCID-responsible gene. We isolated an ORF of the murine DNA-PKcs gene from SCID mice and their parent strain C.B-17 mice and determined the DNA sequences. The ORF of the murine DNA-PKcs gene contained 4128-aa residues and had 78.9% homology with the human DNA-PKcs gene. A particularly important finding is that a T to A transversion results in the substitution of termination codon in SCID mice for the Tyr-4046 in C.B-17 mice. No other mutation was detected in the ORF of the gene. The generality of this transversion was confirmed using four individual SCID and wild-type mice. The substitution took place in the phosphatidylinositol 3-kinase domain, and the mutated gene encodes the truncated products missing 83 residues of wild-type DNA-PKcs products. Furthermore, the quantity of DNA-PKcs transcript in wild-type and SCID cells was almost equal. These observations indicate that the DNA-PKcs gene is the SCID-responsible gene itself and that the detected mutation leads to the SCID aberration.
authors.affiliation: National Institute of Radiological Sciences, Inage-ku, Chiba, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Araki
authors.forename: A
authors.initials: A
authors.lastname: Fujimori
authors.forename: K
authors.initials: K
authors.lastname: Hamatani
authors.forename: K
authors.initials: K
authors.lastname: Mita
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: R
authors.initials: R
authors.lastname: Fukumura
authors.forename: M
authors.initials: M
authors.lastname: Morimyo
authors.forename: M
authors.initials: M
authors.lastname: Muto
authors.forename: M
authors.initials: M
authors.lastname: Itoh
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.forename: M
authors.initials: M
authors.lastname: Abe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003062:Codon; D017931:DNA Primers; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D015870:Gene Expression; D015723:Gene Library; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016366:Open Reading Frames; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine
chemical_list: D003062:Codon; D017931:DNA Primers; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D014443:Tyrosine; C497263:PRKDC protein, human; C497264:Prkdc protein, mouse