Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome
Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome
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DOI：
10.1093/hmg/ddi075
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发表时间：
2005-03-15
影响因子：
3.5
通讯作者：
Luo, G
中科院分区：
文献类型：
--
作者：
Mann, MB;Hodges, CA;Luo, G
II 型罗斯蒙德-汤姆森综合征（II 型 RTS）是一种罕见的常染色体隐性遗传病，其特征是先天性皮疹、骨骼出生缺陷、基因组不稳定和癌症易感性。它是由 RECQL4 基因突变引起的，因此代表了由 RecQ 解旋酶编码基因突变引起的三种易患癌症的遗传病之一。基因组不稳定性被怀疑是这种疾病的一个主要根本原因，对 II 型 RTS 患者来源的细胞的分析表明染色体畸变的频率异常高，表明与染色体不稳定性有关。然而，RECQL4 突变引起的不稳定性的性质尚未明确定义。我们创建了一个可行的 Recql4 突变小鼠模型。这些小鼠表现出独特的皮肤异常、骨骼系统的先天缺陷、基因组不稳定以及在致敏遗传背景下癌症易感性增加。因此，它们为研究 II 型 RTS 提供了一个有用的模型。此外，我们证明来自这些突变小鼠的细胞具有高频率的过早着丝粒分离和非整倍性。因此，我们的观察结果为 Recql4 在姐妹染色单体凝聚力中发挥先前未曾怀疑的作用提供了证据，并表明染色体不稳定性可能是这些突变小鼠的癌症易感性和出生缺陷的根本原因。
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.