Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(6):813-825; doi:10.1093/hmg/ddi075
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Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund–Thomson syndrome
1Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA, 2Case Comprehensive Cancer Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA and 3Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA
* To whom correspondence should be addressed at: Department of Genetics, Case Western Reserve University, BRB 7th Floor, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Tel: +1 2168447050; Fax: +1 2163683432; Email: gxl35{at}case.edu
Received December 17, 2004; Accepted January 25, 2005
Type II Rothmund–Thomson syndrome (Type II RTS) is a rare autosomal recessive genetic disorder characterized by a congenital skin rash, birth defects of the skeleton, genomic instability and cancer predisposition. It is caused by mutations in the RECQL4 gene and thus represents one of the three cancer-prone genetic diseases that are caused by mutations in a RecQ helicase-encoding gene. Genomic instability has been suspected as a major underlying cause of this disease, and analyses of Type II RTS patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations, suggesting the involvement of chromosomal instability. However, the nature of the instability induced by RECQL4 mutations has not been clearly defined. We created a viable Recql4 mutant mouse model. These mice exhibit a distinctive skin abnormality, birth defects of the skeletal system, genomic instability and increased cancer susceptibility in a sensitized genetic background. Thus, they provide a useful model for studying Type II RTS. In addition, we demonstrate that cells from these mutant mice have high frequencies of premature centromere separation and aneuploidy. Thus, our observations provide evidence for a previously unsuspected role for Recql4 in sister-chromatid cohesion, and suggest that the chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.
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