Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination

K Imai, G Slupphaug, WI Lee, P Revy… - Nature …, 2003 - nature.com
K Imai, G Slupphaug, WI Lee, P Revy, S Nonoyama, N Catalan, L Yel, M Forveille, B Kavli…
Nature immunology, 2003nature.com
Activation-induced cytidine deaminase (AID) is a'master molecule'in immunoglobulin (Ig)
class-switch recombination (CSR) and somatic hypermutation (SHM) generation, AID
deficiencies are associated with hyper-IgM phenotypes in humans and mice. We show here
that recessive mutations of the gene encoding uracil–DNA glycosylase (UNG) are
associated with profound impairment in CSR at a DNA precleavage step and with a partial
disturbance of the SHM pattern in three patients with hyper-IgM syndrome. Together with the …
Abstract
Activation-induced cytidine deaminase (AID) is a 'master molecule' in immunoglobulin (Ig) class-switch recombination (CSR) and somatic hypermutation (SHM) generation, AID deficiencies are associated with hyper-IgM phenotypes in humans and mice. We show here that recessive mutations of the gene encoding uracil–DNA glycosylase (UNG) are associated with profound impairment in CSR at a DNA precleavage step and with a partial disturbance of the SHM pattern in three patients with hyper-IgM syndrome. Together with the finding that nuclear UNG expression was induced in activated B cells, these data support a model of CSR and SHM in which AID deaminates cytosine into uracil in targeted DNA (immunoglobulin switch or variable regions), followed by uracil removal by UNG.
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