Abstract
We previously reported a Japanese girl with the novel chromosomal instability syndrome. The clinical symptoms included severe microcephaly, short stature, combined immunodeficiency, and development of malignant lymphoma. The primary skin fibroblast from the patient showed increased spontaneous chromosome breakages and radiation hypersensitivity. The clinical and cellular phenotypes were similar to those of the patients with Nijmegen breakage syndrome (NBS). However, no mutation was detected in the NBS1 gene, and western blot revealed normal expression of NBS1, Mre11, and Rad50 proteins. In addition, the cells showed the irradiation-induced focus formation at the similar level to that of normal cells.
To identify the underlying gene for the patient, we utilized the technique of microcell-mediated chromosome transfer (MMCT) to introduce a human chromosome into the patient’s fibroblast cell line, and functional complementation assays were carried out. We found that a chromosome 13 complemented the radiation hypersensitivity of the patient’s cells. Since the chromosome 13 contains the DNA ligase IV (LIG4) gene, which is involved in non-homologous end joining pathway of DNA DSB repair, mutation screening was performed in the LIG4 gene of the patient, and biallelic mutations were detected in the LIG4 gene. These results demonstrated that this is the first Japanese patient with the LIG4 syndrome.
