Molecular cytogenetic study on the genetic trait of mitotic checkpoint impairment

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(1) Infants homozygous for the premature chromatid separation (PCS : OMIM#176430) trait are characterized by mosaic variegated aneuploidy and severe clinical manifestations such as growth retardation, microcephaly, brain hypoplasia, and development of Wilms tumor (Kajii et al., 1998). Fifbroblasts from patients with PCS syndrome show impairment of the mitotic spindle checkpoint (Matsuura et al., 2001). A review of the clinical manifestations and chromosomal data in 10 cases of PCS including the 5 newly detected infants showed that homozygosity for the PCS trait is an established clinical entity characterized by susceptibility to cancer and chromosomal instability syndrome due to impairment of mitotic spindle checkpoint (Kajii et all., 2001).(2) Amniocentesis was performed at 15 wks of pregnancy because of previous deliveries of two PCS infants, and the obtained PCS frequencies (4.5%) suggested that the fetus was heterozygous for the trait. This indicates that prenatal diagnosis of both … More hetero-and homozygosity for the PCS trait is possible (Kajii & Asamoto, 2004).(3) Definition of the term "PCS" was clarified from the standpoints of its configuration and pathological significance, with special emphasis on the diffenence from the term "PCD (premature centromere division : OMIM#212790)" which involves the X chromosome exclusively (Kajii & Ikeuchi, 2004).(4) The frequency of cells in PCS is the most important hallmark for diagnosis of PCS syndrome. Hypotonic treatment of cells at 37℃ for 20 min was found to be most suitable among the conditions tested for the detection of PCS in individuals with the homozygous or heterozygous for the PCS trait (Ikeuchi et al., 2004).(5) Chromomal and DNA polymorphic marker studies revealed that the tumors developing in PCS patients had uniparental (paternal) disomy for chromosome 11, suggesting that the increased dosage of imprinted genes such as paternally expressed IGF2 was primarily involved in tumor development.(6) Lymphoblastoid cell lines (LCLs) and fibroblasts derived from the two PCS patients and a number of LCLs from heterozygous carriers were established and stored. Less