2. Academic Validation
  3. Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia

Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia

  • Cell Mol Gastroenterol Hepatol. 2015 Jul;1(4):381-394.e7. doi: 10.1016/j.jcmgh.2015.05.001.
Abdul Elkadri 1,  Cornelia Thoeni 2,  Sophie J Deharvengt 3,  Ryan Murchie 2,  Conghui Guo 4,  James D Stavropoulos 5,  Christian R Marshall 5,  Paul Wales 6,  Robert Bandsma 4,  Ernest Cutz 7,  Chaim M Roifman 8,  David Chitayat 9,  Yaron Avitzur 6,  Radu V Stan 3,  Aleixo M Muise 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Pathology, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA.
  • 4 Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
  • 5 Genome Diagnostics, Department of Paediatric Laboratory Medicine The Hospital for Sick Children, Toronto, ON, Canada.
  • 6 Group for Improvement of Intestinal Function and Treatment (GIFT), Hospital for Sick Children, Toronto, Ontario, Canada.
  • 7 Division of Pathology, The Hospital for Sick Children, Toronto, Canada.
  • 8 Division of Immunology, Department of Pediatrics, University of Toronto The Hospital for Sick Children, Toronto, Canada.
  • 9 Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
  • 10 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.
PMID: 26207260 DOI: 10.1016/j.jcmgh.2015.05.001
Abstract

Background & aims methods: 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 the PLVAP (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.

Keywords

IBD; PLE; PLVAP; Protein losing enteropathy; VEOIBD; and hypertriglyceridemia; endothelium; fenestrae; hypoalbuminemia; hypoproteinemia; monogenic diseases; very early onset IBD.

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