The Molecular Basis of Rothmund-Thomson Syndrome

描述（由申请人提供）：Rothmund-Thomson综合征（RTS）是一种 属于RecQ家族的罕见遗传性染色体不稳定综合征 解旋酶疾病，其特征是皮疹，骨骼 异常，身材矮小，青少年白内障，和一个重大的癌症 易感性，特别是骨肉瘤。 本研究的假设 是对罕见癌症易感综合征，如RTS， 将为基因组学的分子基础提供重要的新见解 稳定性和遗传性和散发性癌症的病因。 广大 该项目的目标是了解分子，临床， RTS的细胞特征。 临床研究结果将对以下方面产生影响： 儿科的许多领域，包括遗传学，皮肤病学，眼科学， 肿瘤学 分子和细胞的发现将有助于 了解其他相关的染色体不稳定综合征，并可能导致 涉及用于诊断RTS的测定。 第一个具体目标涉及 全面的分子分析加上详细的临床描述， RTS患者入组IRB批准的一般临床研究中心 贝勒医学院（Baylor College of Medicine） 基因突变的筛查 将通过基因组DNA测序和DHPLC筛选进行RECQL 4基因 先证者的cDNA。 基因型/表型关联将由 临床和分子数据。 第二个具体目标将涉及 研究RTS中目前未知的细胞缺陷。 响应 RTS细胞对各种导致DNA损伤或复制的试剂的敏感性 将分析组织块的敏感性和细胞周期 进展 通过研究解旋酶的基本缺陷， 范式障碍，如RTS可能提供深入了解癌症的机制， 发病机制，并可能有重要的临床意义，在管理 这些病人。 这个指导临床科学家发展奖将 作为一种工具，让候选人完成她的即时培训 目标在一个指导的科学环境，并达到候选人的 作为儿科肿瘤学的医生科学家的长期职业目标。 的 导师和一流的设施和资源，将提供理想的 在K 08奖项所涵盖的时期内，候选人的环境。 这一经验将提供基础， 候选人作为独立调查员的职业生涯。

DESCRIPTION (provided by applicant): Rothmund-Thomson syndrome (RTS) is a rare inherited, chromosomal instability syndrome belonging to the RecQ family of helicase disorders, and is characterized by skin rash, skeletal abnormalities, small stature, juvenile cataracts, and a significant cancer predisposition, particularly for osteosarcoma. The hypothesis of this study is that detailed study of rare cancer predisposition syndromes, such as RTS, will provide significant new insights into the molecular basis of genomic stability and the etiology of both inherited and sporadic cancers. The broad objectives of this project are to understand the molecular, clinical, and cellular features of RTS. The clinical findings will have implications in many areas of pediatrics, including genetics, dermatology, ophthalmology, and oncology. The molecular and cellular findings will contribute to understanding of other related chromosome instability syndromes and may lead to an assay for the diagnosis of RTS. The first specific aim involves comprehensive molecular analysis coupled with detailed clinical description of RTS patients enrolled in an IRB-approved General Clinical Research Center study at Baylor College of Medicine (BCM). Screening for mutations in the RECQL4 gene will be performed by sequencing of genomic DNA and DHPLC screening of cDNA in probands. Genotype/phenotype associations will be generated from clinical and molecular data. The second specific aim will involve investigation of the presently unknown cellular defects in RTS. The response of RTS cells to a variety of agents that cause DNA damage or replication blocks will be analyzed with respect to sensitivity and cell cycle progression. Understanding the basic helicase defect through study of paradigm disorders such as RTS may provide insight into mechanisms of cancer pathogenesis and may have important clinical implications in the management of these patients. This Mentored Clinical Scientist Development Award would serve as a vehicle to allow the candidate to accomplish her immediate training goals in a mentored scientific environment, and to reach the candidate's long-term career goals as a physician-scientist in pediatric oncology. The mentor and the superb facilities and resources at BCM will provide the ideal environment for the candidate during the period covered by the K08 award. This experience will provide the foundation upon which to build the candidate's career as an independent investigator.