Author:
Park Jong Eun,Kim Eunmi,Lee Dong-Won,Park Taek Kyu,Kim Min Sun,Jang Shin Yi,Ahn Jaemyung,Park Kwang Bo,Kim Keon-Ha,Park Hae-Chul,Ki Chang-Seok,Kim Duk-Kyung
Abstract
AbstractRubinstein–Taybi syndrome (RSTS) is a human genetic disorder characterized by distinctive craniofacial features, broad thumbs and halluces, and intellectual disability. Mutations in the CREB binding protein (CREBBP) and E1A binding protein p300 (EP300) are the known causes of RSTS disease. EP300 regulates transcription via chromatin remodeling and plays an important role in cell proliferation and differentiation. Plasminogen activator, urokinase (PLAU) encodes a serine protease that converts plasminogen to plasmin and is involved in several biological processes such as the proteolysis of extracellular matrix-remodeling proteins and the promotion of vascular permeability and angiogenesis. Recently, we discovered a patient who presented with RSTS-related skeletal anomaly and peripheral arterial vasculopathy. To investigate the genetic cause of the disease, we performed trio whole genome sequencing of the genomic DNA from the proband and the proband’s parents. We identified two de novo variants coined c.1760T>G (p.Leu587Arg) and c.664G>A (p.Ala222Thr) in EP300 and PLAU, respectively. Furthermore, functional loss of EP300a and PLAUb in zebrafish synergistically affected the intersegmental vessel formation and resulted in the vascular occlusion phenotype. Therefore, we hypothesize that the de novo EP300 variant may have caused RSTS, while both the identified EP300 and PLAU variants may have contributed to the patient’s vascular phenotype.
Funder
National Research Foundation of Korea
Publisher
Springer Science and Business Media LLC
Reference27 articles.
1. Hennekam, R. C. Rubinstein–Taybi syndrome. Eur. J. Hum. Genet. 14, 981–985 (2006).
2. Stevens, C. A. Rubinstein–Taybi syndrome. In GeneReviews® (eds Adam, M. P. et al.) (University of Washington, 1993–2021).
3. Giles, R. H., Peters, D. J. & Breuning, M. H. Conjunction dysfunction: CBP/p300 in human disease. Trends Genet. 14, 178–183 (1998).
4. Delvecchio, M., Gaucher, J., Aguilar-Gurrieri, C., Ortega, E. & Panne, D. Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. Nat. Struct. Mol. Biol. 20, 1040–1046 (2013).
5. Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24, 300–303 (2000).
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