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

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....

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Autores principales:	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
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Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/167beca6d7ac4a52a04ac39d45dbcaeb
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spelling	oai:doaj.org-article:167beca6d7ac4a52a04ac39d45dbcaeb2021-12-02T14:53:48ZIdentification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly10.1038/s41598-021-95133-02045-2322https://doaj.org/article/167beca6d7ac4a52a04ac39d45dbcaeb2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95133-0https://doaj.org/toc/2045-2322Abstract 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.Jong Eun ParkEunmi KimDong-Won LeeTaek Kyu ParkMin Sun KimShin Yi JangJaemyung AhnKwang Bo ParkKeon-Ha KimHae-Chul ParkChang-Seok KiDuk-Kyung KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
description	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.
format	article
author	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
author_facet	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
author_sort	Jong Eun Park
title	Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
title_short	Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
title_full	Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
title_fullStr	Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
title_full_unstemmed	Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly
title_sort	identification of de novo ep300 and plau variants in a patient with rubinstein–taybi syndrome-related arterial vasculopathy and skeletal anomaly
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/167beca6d7ac4a52a04ac39d45dbcaeb
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Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly

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