title: Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia.
abstract: Severe intestinal diseases observed in very young children are often the result of monogenic defects. We used whole exome sequencing (WES) to examine the genetic cause in a patient with a distinct severe form of protein losing enteropathy (PLE) characterized by hypoproteinemia, hypoalbuminemia, and hypertriglyceridemia.
  
  
  METHODS
  WES was performed at the Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada. Exome library preparation was performed using the Ion Torrent AmpliSeq RDY Exome Kit. Functional studies were carried out based on the identified mutation.
  
  
  RESULTS
  Using whole exome sequencing we identified a homozygous nonsense mutation (1072C>T; p.Arg358*) in thePLVAP(plasmalemma vesicle associated protein) gene in an infant from consanguineous parents who died at five months of age of severe protein losing enteropathy. Functional studies determined that the mutated PLVAP mRNA and protein were not expressed in the patient biopsy tissues, presumably secondary to nonsense-mediated mRNA decay. Pathological analysis showed that the loss of PLVAP resulted in disruption of endothelial fenestrated diaphragms.
  
  
  CONCLUSIONS
  PLVAP p.Arg358* mutation resulted in loss of PLVAP expression with subsequent deletion of the diaphragms of endothelial fenestrae leading to plasma protein extravasation, protein-losing enteropathy and ultimately death.
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada ; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada ; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Elkadri
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada ; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Thoeni
authors.affiliation: Department of Pathology, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Deharvengt
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada ; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murchie
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Conghui
authors.initials: C
authors.lastname: Guo
authors.affiliation: Genome Diagnostics, Department of Paediatric Laboratory Medicine The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Stavropoulos
authors.affiliation: Genome Diagnostics, Department of Paediatric Laboratory Medicine The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Wales
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bandsma
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cutz
authors.affiliation: Division of Immunology, Department of Pediatrics, University of Toronto The Hospital for Sick Children, Toronto, Canada.
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.affiliation: Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Avitzur
authors.affiliation: Department of Pathology, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA.
authors.forename: Radu V
authors.initials: RV
authors.lastname: Stan
authors.affiliation: SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada ; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada ; Institute of Medical Science, University of Toronto, Toronto, ON, Canada ; Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
keywords: IBD; PLE; PLVAP; Protein losing enteropathy; VEOIBD; and hypertriglyceridemia; endothelium; fenestrae; hypoalbuminemia; hypoproteinemia; monogenic diseases; very early onset IBD