The Molecular Basis of Rothmund-Thomson Syndrome

描述(申请人提供)：Rothmund-Thomson综合征(RTS)是 属于RecQ家族的罕见遗传性染色体不稳定综合征 解旋酶紊乱，其特征是皮疹，骨骼 畸形、身材矮小、青少年白内障和严重的癌症 易患此病，尤其是骨肉瘤。这项研究的假设是 是对罕见癌症易感综合征的详细研究，如RTS， 将为基因组的分子基础提供重要的新见解 遗传性和散发性癌症的稳定性和病因学。《博大》 本项目的目标是了解分子、临床和 RTS的细胞特征。这一临床发现将对 儿科的许多领域，包括遗传学、皮肤科、眼科和 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 建立了一种诊断RTS的方法。第一个具体目标包括 全面的分子分析和详细的临床描述 在IRB批准的综合临床研究中心登记的RTS患者 在贝勒医学院(BCM)学习。基因突变的筛查 RECQL4基因将通过基因组DNA测序和DHPLC筛选来进行 在先证者中。将从以下方面产生基因/表型关联 临床和分子数据。第二个具体目标将涉及 RTS中目前未知的细胞缺陷的研究。他们的回应 对引起DNA损伤或复制的各种因素的影响 将从灵敏度和细胞周期两个方面分析数据块 进步。通过对碱性解旋酶缺陷的研究了解其缺陷 RTS等范式障碍可能为癌症的发病机制提供洞察 发病机制，并可能在治疗中具有重要的临床意义 这些病人。这项指导临床科学家发展奖将 作为应聘者立即完成培训的载体 在有指导的科学环境中实现目标，并达到候选人的 长期的职业目标是成为一名儿科肿瘤学的内科科学家。这个 Mentor和BCM一流的设施和资源将提供理想的 在K08奖项所涵盖的期间为候选人提供的环境。 这一经验将提供基础，以建立 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.