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LIG4 syndrome

Ligase IV (LIG4) syndrome belongs to the group of hereditary disorders associated with impaired DNA damage response mechanisms. Clinically and morphologically, patients affected with this syndrome are characterized by microcephaly, unusual facial features, growth retardation, developmental delay, skin anomalies and are typically pancytopenic. The disease leads to acute radiosensitivity, immunodeficiency and bone marrow abnormalities.

LIG4 syndrome arises from hypomorphic mutations in the LIG4 gene at 13q22-q34 (MIM.601837) encoding DNA ligase IV; a component of the nonhomologous end‑joining machinery, which represents a major mechanism of repair of double strand DNA breaks in mammals. The hypomorphic mutations do not completely abolish but significantly reduce enzyme function. This results in impaired V(D)J recombination, the essential rejoining process in T and B cell development, in whose ligase IV plays the key role. As a consequence, patients with LIG4 syndrome frequently develop multiple immune abnormalities, clinically overlapping with severe combined immunodeficiency syndrome (SCID). Moreover, the clinical phenotype of the LIG4 syndrome closely shows overlap with a number of other rare syndromes of the DNA damage response disorders, including Nijmegen breakage syndrome (NBS; 251260), Seckel syndrome, and Fanconi disease (Fanconi anemia). 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.

ABREVIATION(S):
LIG4S
LIG4

TYPE: mental retardation (MR), psychomotor impairment, skeletal abnormalities, risk of malignant disease, skin problem, chromosomal instability, immunodeficiency, sensitivity to radiation, facial anomalies, growth retardation, microcephaly

Related patway(s): non-homologous end-joining (NHEJ)

DNAtraffic protein(s) related to disease: LIG4

OMIM: 606593

Last modification date: Aug. 17, 2011