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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Coulombe, James N
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Baylor College of Medicine
Schools of Medicine
United States
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Jewell, Brittany E; Liu, Mo; Lu, Linchao et al. (2018) Generation of an induced pluripotent stem cell line from an individual with a heterozygous RECQL4 mutation. Stem Cell Res 33:36-40
Cao, Felicia; Lu, Linchao; Abrams, Steven A et al. (2017) Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Hum Mol Genet 26:3046-3055
Clericuzio, Carol; Harutyunyan, Karine; Jin, Weidong et al. (2011) Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia. Am J Med Genet A 155A:337-42
Siitonen, H Annika; Sotkasiira, Jenni; Biervliet, Martine et al. (2009) The mutation spectrum in RECQL4 diseases. Eur J Hum Genet 17:151-8
Jin, Weidong; Liu, Hao; Zhang, Yiqun et al. (2008) Sensitivity of RECQL4-deficient fibroblasts from Rothmund-Thomson syndrome patients to genotoxic agents. Hum Genet 123:643-53
Mehollin-Ray, Amy R; Kozinetz, Claudia A; Schlesinger, Alan E et al. (2008) Radiographic abnormalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status. AJR Am J Roentgenol 191:W62-6
Hicks, M John; Roth, Jill R; Kozinetz, Claudia A et al. (2007) Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol 25:370-5
Wang, Lisa L; Gannavarapu, Anu; Clericuzio, Carol L et al. (2003) Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-Navajo patients. Am J Med Genet A 118A:299-301
Wang, Lisa L; Gannavarapu, Anu; Kozinetz, Claudia A et al. (2003) Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 95:669-74