International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

WEDNESDAY OCTOBER 20

8.00pm – 8.15pm

CHROMOSOMAL INSTABILITY LEADS TO BIRTH DEFECTS AND CANCER PREDISPOSITION IN RECQL4-DEFICIENT MICE: A MODEL OF ROTHMUND-THOMSON SYNDROME

Mann MB, Luo G

Department of Genetics, Case Western Reserve University and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, United States

Rothmund-Thomson Syndrome (RTS) is a genetically heterogeneous autosomal recessive disorder.  Type-II RTS patients have RECQL4 mutations, abnormalities of the skin and skeleton and increased risk for developing osteosarcoma.  Karyotypic analyses of type II patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations including aneuploidy.  While chromosomal instability likely contributes to the patients increased susceptibility to osteosarcoma, the nature of genomic instability induced by RECQL4 deficiency and the disease etiology of RTS remains elusive.  We generated Recql4-deficient mice to study the role of Recql4 in maintaining genomic stability.  Recql4-deficient mice recapitulate the hallmark features of RTS with skeletal abnormalities of the palate and limbs, ultraviolet light induced hyperpigmentation associated with premature photoaging and increased susceptibility to osteosarcoma and lymphoma.  Cells from Recql4-deficient mice display aneuploidy and chromosomal instability with an increased incidence of anaphase lagging chromosomes and high rates of spontaneous micronuclei formation.  Remarkably, in Recql4-deficient cells, aneuploidy manifests in the absence of defects in spindle checkpoints or aberrant centrosomes hyperamplification.  Further analysis revealed that premature centromere separation induced unequal chromosome partitioning is the underlying mechanism leading to aneuploidy in Recql4-deficient cells. Thus, we conclude that Recql4 has a role in mitotic chromosome segregation and maintenance of genome stability. This is the first documentation of this mechanism for the production of aneuploidy in mammalian cells. Our findings also provide the first evidence that in mammals, as in unicellular organisms, the RecQ family of DNA helicases have an important role in chromosome segregation.

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