Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly

Jong Eun Park, Eunmi Kim, Dong Won Lee, Taek Kyu Park, Min Sun Kim, Shin Yi Jang, Jaemyung Ahn, Kwang Bo Park, Keon Ha Kim, Hae Chul Park, Chang Seok Ki, Duk Kyung Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Rubinstein–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.

Original languageEnglish
Article number15931
JournalScientific reports
Volume11
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • General

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