Genomic instability, cancer predisposition and premature aging in a mouse model of Rothmund-Thomson Syndrome

RecQ DNA helicases have important roles in the maintenance of genome stability. Recql4, one of five mammalian RecQ DNA helicases, is the mouse orthologue of the disease-causing gene, RECQL4, of Type II Rothmund-Thomson Syndrome (RTS). Type-II RTS patients have 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, and demonstrate here that they are viable and manifest the hallmark features of RTS, including developmental defects of skeleton, skin pigmentation defects, genomic instability and predisposition to cancer. Specifically, Recql4-deficient mice have skeletal defects of the palate and limbs, display premature onset degenerative joint defects and osteoporosis, spontaneously acquire several abnormalities of the skin, including premature alopecia and graying of fur. One striking skin phenotype is an induced hyper-pigmentation associated with premature photo-aging upon treatment with low dose ultraviolet light. Cellular analyses derived from these mice revealed defects in chromosome segregation and aneuploidy resulting from precocious loss of sister-chromatid cohesion. Thus, mammalian Recql4 has a critical role in sister-chromatid cohesion and in the maintenance of euploidy and that Recql4-deficient mice manifest a premature aging-like syndrome that shares phenotypic features with RTS patients and the elderly.