Lig4 Syndrome
A number sign (#) is used with this entry because LIG4 syndrome is caused by homozygous or compound heterozygous mutation in the LIG4 gene (601837) on chromosome 13q33.
Clinical FeaturesO'Driscoll et al. (2001) identified 4 patients with features including immunodeficiency and developmental and growth delay who had mutations in the LIG4 gene (see MOLECULAR GENETICS). The clinical phenotype, which they called LIG4 syndrome, closely resembled the DNA damage response disorder Nijmegen breakage syndrome (NBS; 251260). All 4 patients displayed unusual facial features, microcephaly, growth and/or developmental delay, pancytopenia, and various skin abnormalities. Cell lines from the patients showed pronounced radiosensitivity. Unlike NBS cell lines, they showed normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype was observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.
Ben-Omran et al. (2005) reported a 4-year-old boy with acute T-cell leukemia and a facial gestalt reminiscent of NBS. Chromosomal breakage studies showed a high rate of breakage in a fibroblast culture; radiosensitivity was greater than is typically seen in NBS.
Van der Burg et al. (2006) reported a patient with severe combined immunodeficiency with sensitivity to ioninzing radiation. The patient, born of consanguineous Turkish parents, developed severe recurrent infections and candidiasis in the second year of life. She had no dysmorphic features or neurologic abnormalities. Laboratory analysis showed decreased immunoglobulins, reduced numbers of B and T cells, normal levels of NK cells, and almost undetectable levels of the LIG4 protein. Further analysis of patient's cells showed a defect in V(D)J recombination with extensive nucleotide deletions apparently caused by prolonged exonuclease activity during a delayed ligation process.
Molecular GeneticsIn 4 patients with LIG4 syndrome, O'Driscoll et al. (2001) identified homozygous mutations in the LIG4 gene (601837.0001-601837.0004).
Ben-Omran et al. (2005) reported a 4-year-old boy with acute T-cell leukemia and a facial gestalt reminiscent of NBS in whom no mutation was found in the NBS1 gene (602667). Sequencing of the LIG4 gene revealed homozygosity for a truncating mutation (R814X; 601837.0002).
Girard et al. (2004) showed that the clinical severity among 5 patients with LIG4 syndrome correlated with the level of residual ligase activity. Two linked polymorphisms (A3V, 601837.0005; T9I, 601837.0006) were found to decrease the activity of DNA ligase IV by approximately 2-fold. When combined with the otherwise mild R278H (601837.0004) mutation, ligase activity was reduced to a level similar to that of LIG4 patients with immunodeficiency and developmental delay.
In a patient with LIG4 syndrome, van der Burg et al. (2006) identified a homozygous mutation in the LIG4 gene (601837.0007).
Animal ModelRucci et al. (2010) found that transgenic mice carrying a homozygous R278H Lig4 mutation (601837.0004) had growth retardation, decreased life span, decreased fertility, severe cellular sensitivity to ionizing radiation, and a severe, but incomplete, defect in V(D)J recombination in immune cells with an incomplete block in B- and T-cell development. The thymus and the spleen were small, with decreased numbers of T cells. Peripheral T lymphocytes showed an activated and anergic phenotype, reduced viability, and a restricted repertoire, whereas B cells produced low-affinity antibodies that include autoreactive specificities. However, mutant mice were unable to mount high-affinity antibody responses. The mice showed a high frequency of thymic tumors associated with genomic instability. The phenotype was reminiscent of leaky human severe combined immunodeficiency (SCID).