PUBLICATION
Identification of de novo EP300 and PLAU variants in a patient with Rubinstein-Taybi syndrome-related arterial vasculopathy and skeletal anomaly
- Authors
- Park, J.E., Kim, E., Lee, D.W., Park, T.K., Kim, M.S., Jang, S.Y., Ahn, J., Park, K.B., Kim, K.H., Park, H.C., Ki, C.S., Kim, D.K.
- ID
- ZDB-PUB-210807-3
- Date
- 2021
- Source
- Scientific Reports 11: 15931 (Journal)
- Registered Authors
- Park, Hae-Chul
- Keywords
- none
- MeSH Terms
-
- Adult
- Animals
- Bone and Bones/metabolism
- Disease Models, Animal
- E1A-Associated p300 Protein/genetics*
- E1A-Associated p300 Protein/metabolism
- Family
- Female
- Genetic Association Studies
- Humans
- Male
- Membrane Proteins/genetics*
- Membrane Proteins/metabolism
- Musculoskeletal Abnormalities/genetics
- Mutation
- Phenotype
- Rubinstein-Taybi Syndrome/genetics*
- Sequence Deletion
- Zebrafish
- PubMed
- 34354133 Full text @ Sci. Rep.
Citation
Park, J.E., Kim, E., Lee, D.W., Park, T.K., Kim, M.S., Jang, S.Y., Ahn, J., Park, K.B., Kim, K.H., Park, H.C., Ki, C.S., Kim, D.K. (2021) Identification of de novo EP300 and PLAU variants in a patient with Rubinstein-Taybi syndrome-related arterial vasculopathy and skeletal anomaly. Scientific Reports. 11:15931.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping