title: DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia.
abstract: Previously, spontaneous genetic immunodeficiencies in mice, Arabian foals, and recently in Jack Russell terriers have been ascribed to defects in DNA-PKcs (catalytic subunit of the DNA dependent protein kinase) expression. In severe combined immunodeficiency (SCID) foals, a 5 bp deletion at codon 9480 results in a frameshift and a 967 amino acid deletion from the C terminus (including the entire PI3 kinase domain) and an unstable mutant protein. In SCID mice, a single base pair mutation results in a premature stop codon and deletion of 83 amino acids; as in SCID foals, the mutant protein is unstable. Here, we define the mutation within the canine DNA-PKcs gene that results in SCID. In this case, a point mutation results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele. Thus, this is the third documentation of a spontaneous germline mutation in the C terminus of DNA-PKcs. Emerging data implicate DNA repair factors as potential tumor suppressors. Here, we have ascertained the carrier frequency of the defective DNA-PKcs genes in Arabian horses and in Jack Russell terriers. Our data indicate (in good agreement with a previous report) that the carrier frequency of the equine SCID allele is approximately 8%; in contrast, the carrier frequency of the canine SCID allele is less than 1.1%. We also assessed the frequency of the equine SCID allele in a series of 295 tumors from Arabian horses. We find a statistically significant correlation between the development of a virally induced tumor (sarcoid) and heterozygosity for the equine SCID allele. These data provide further support for an emerging consensus: that DNA-PK may normally act as a tumor suppressor through its caretaker role in maintaining chromosomal stability.
authors.affiliation: College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ding
authors.forename: Lori
authors.initials: L
authors.lastname: Bramble
authors.forename: Vilma
authors.initials: V
authors.lastname: Yuzbasiyan-Gurkan
authors.forename: Thomas
authors.initials: T
authors.lastname: Bell
authors.forename: Katheryn
authors.initials: K
authors.lastname: Meek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain / Q000235:genetics*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004285:Dogs; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006736:Horses; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases