PUBLICATION
Mosaic partial deletion of PTPN12 in a child with interrupted aortic arch type A
- Authors
- Duffy, E.A., Pretorius, P.R., Lerach, S., Lohr, J.L., Hirsch, B., Souza, C.M., Veillette, A., Schimmenti, L.A.
- ID
- ZDB-PUB-150808-6
- Date
- 2015
- Source
- American journal of medical genetics. Part A 167(11): 2674-83 (Journal)
- Registered Authors
- Lerach, Stephanie, Pretorius, Pamela, Schimmenti, Lisa A.
- Keywords
- PTPN12, interrupted aortic arch, vascular development, zebrafish
- MeSH Terms
-
- Adult
- Amino Acid Sequence
- Angiography
- Animals
- Aorta, Thoracic/abnormalities*
- Aorta, Thoracic/diagnostic imaging
- Aorta, Thoracic/embryology
- Aorta, Thoracic/pathology*
- Child
- Comparative Genomic Hybridization
- Conserved Sequence
- Embryonic Development
- Gene Knockdown Techniques
- Humans
- In Situ Hybridization, Fluorescence
- Infant
- Infant, Newborn
- Larva
- Male
- Mice
- Molecular Sequence Data
- Mosaicism*
- Neovascularization, Physiologic
- Phenotype
- Protein Tyrosine Phosphatase, Non-Receptor Type 12/chemistry
- Protein Tyrosine Phosphatase, Non-Receptor Type 12/genetics*
- Sequence Alignment
- Sequence Deletion*
- Tomography, X-Ray Computed
- Zebrafish/embryology
- PubMed
- 26250342 Full text @ Am. J. Med. Genet. A
Citation
Duffy, E.A., Pretorius, P.R., Lerach, S., Lohr, J.L., Hirsch, B., Souza, C.M., Veillette, A., Schimmenti, L.A. (2015) Mosaic partial deletion of PTPN12 in a child with interrupted aortic arch type A. American journal of medical genetics. Part A. 167(11):2674-83.
Abstract
Congenital heart malformations, including those of the great vessels, are among the most common human birth defects. The goal of this study was to identify the significance of a de novo mosaic PTPN12 partial deletion identified in a newborn with an interrupted aortic arch type A, ventricular septal defect, and pyloric stenosis. PTPN12, a downstream target of the RAS pathway, has a known role in endothelial cell adhesion and migration. Neither genetic nor genomic variants in PTPN12 have been described in a human patient; therefore, we evaluated the effect of ptpn12 in a mouse conditional knockout and zebrafish knockdown model to determine the significance of a loss in gene expression. Observed loss of ptpn12 expression in zebrafish resulted in abnormal branchial arch and tail vasculature patterns, with reduced blood flow throughout the animal. This phenotype was supported by anomalous vasculature in a conditional Ptpn12 mouse knockout. Given the novel co-occurrence of interrupted aortic arch type A, ventricular septal defect, and partial deletion of PTPN12 in the patient, as well as vascular phenotypes in Ptpn12 mouse and ptpn12 zebrafish models, it is likely that PTPN12 has a significant role in cardiovascular development and vessel formation during human embryonic development. Furthermore, the partial deletion of PTPN12 lead to interrupted aortic arch type A in this child and may represent a novel condition caused by a null mutation in the RAS pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping