title: DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency.
abstract: DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.
authors.affiliation: Genome Damage and Stability Unit, University of Sussex, Brighton, East Sussex, BN1 9RR, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: K M
authors.initials: KM
authors.lastname: Cerosaletti
authors.forename: P M
authors.initials: PM
authors.lastname: Girard
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.forename: M
authors.initials: M
authors.lastname: Stumm
authors.forename: B
authors.initials: B
authors.lastname: Kysela
authors.forename: B
authors.initials: B
authors.lastname: Hirsch
authors.forename: A
authors.initials: A
authors.lastname: Gennery
authors.forename: S E
authors.initials: SE
authors.lastname: Palmer
authors.forename: J
authors.initials: J
authors.lastname: Seidel
authors.forename: R A
authors.initials: RA
authors.lastname: Gatti
authors.forename: R
authors.initials: R
authors.lastname: Varon
authors.forename: M A
authors.initials: MA
authors.lastname: Oettinger
authors.forename: H
authors.initials: H
authors.lastname: Neitzel
authors.forename: P A
authors.initials: PA
authors.lastname: Jeggo
authors.forename: P
authors.initials: P
authors.lastname: Concannon
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D019457:Chromosome Breakage / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics*; D005347:Fibroblasts; D015321:Gene Rearrangement / Q000235:genetics; D005816:Genetic Complementation Test; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype; D011485:Protein Binding; D011836:Radiation Tolerance / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D013577:Syndrome; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C101467:XRCC4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP