Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promoter and first exon by homologous recombination between two Alu elements.
In 15-20% of children with severe combined immunodeficiency (SCID), the underlying defect is adenosine deaminase (ADA) deficiency. The goal of this study was to determine the precise molecular defect in a patient with ADA-deficient SCID whom we previously have shown to have a total absence of ADA mRNA and a structural alteration of the ADA gene. By detailed Southern analysis, we now have determined that the structural alteration is a deletion of approximately 3.3 kb, which included exon 1 and the promoter region of the ADA gene. DNA sequence analysis demonstrates that the deletion created a novel, complete Alu repeat by homologous recombination between two existing Alu repeats that flanked the deletion. The 26-bp recombination joint in the Alu sequence includes the 10-bp "B" sequence homologous to the RNA polymerase III promoter. This is the first example of homologous recombination involving the B sequence in Alu repeats. Similar recombination events have been identified involving Alu repeats in which the recombination joint was located between the A and B sequences of the polymerase III split promoter. The nonrandom location of these events suggests that these segments may be hot spots for recombination.
Markert
M L
ML
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Hutton
J J
JJ
Wiginton
D A
DA
States
J C
JC
Kaufman
R E
RE
D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics; D001483:Base Sequence; D002872:Chromosome Deletion; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D005091:Exons; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D009700:Nucleoside Deaminases / Q000172:deficiency*; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D012689:Sequence Homology, Nucleic Acid
D004247:DNA; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase