title: Mosaic partial deletion of PTPN12 in a child with interrupted aortic arch type A.
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.
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Duffy
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.|Department of Biology, Hanover College, Hanover, Indiana.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Pretorius
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lerach
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.|Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lohr
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Betsy
authors.initials: B
authors.lastname: Hirsch
authors.affiliation: Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Cleiton M
authors.initials: CM
authors.lastname: Souza
authors.affiliation: Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada.|Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.|Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota.|Department of Ophthalmology and Vision Neuroscience, University of Minnesota, Minneapolis, Minnesota.|Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota.|Developmental Biology Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Schimmenti
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000792:Angiography; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000196:embryology / Q000473:pathology*; D002648:Child; D055028:Comparative Genomic Hybridization; D017124:Conserved Sequence; D047108:Embryonic Development; D055785:Gene Knockdown Techniques; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007814:Larva; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009030:Mosaicism; D018919:Neovascularization, Physiologic; D010641:Phenotype; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D017384:Sequence Deletion; D014057:Tomography, X-Ray Computed; D015027:Zebrafish / Q000196:embryology
chemical_list: C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12
keywords: PTPN12; interrupted aortic arch; vascular development; zebrafish