A severe form of human combined immunodeficiency due to mutations in DNA ligase IV.
DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and alphabeta T cells 10-fold, whereas gammadelta T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of gammadelta T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype.
Enders
Anselm
A
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Fisch
Paul
P
Schwarz
Klaus
K
Duffner
Ulrich
U
Pannicke
Ulrich
U
Nikolopoulos
Elisabeth
E
Peters
Anke
A
Orlowska-Volk
Marzenna
M
Schindler
Detlev
D
Friedrich
Wilhelm
W
Selle
Barbara
B
Niemeyer
Charlotte
C
Ehl
Stephan
S
D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011836:Radiation Tolerance / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
C000607893:LIG4 protein, human; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP