期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 1, 期 4, 页码 381-+出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2015.05.001
关键词
Endothelium; Fenestrae; Hypertriglyceridemia; Hypoalbuminemia; Hypoproteinemia; Very Early Onset Inflammatory Bowel Disease; Monogenic Diseases; Protein-Losing Enteropathy; Whole-Exome Sequencing
资金
- Crohn's and Colitis Canada (CCC)
- Canadian Association of Gastroenterology
- Canadian Institute of Health Research Fellowship
- Research Institute of the Hospital for Sick Children, Toronto, Canada
- National Institutes of Health [CA175592, CA172983, CA023108, S10OD010330]
- CIHR Operating Grant [MOP119457]
- Leona M. and Harry B. Helmsley Charitable Trust
BACKGROUND & AIMS: Severe intestinal diseases observed in very young children are often the result of monogenic defects. We used whole-exome sequencing (WES) to examine genetics 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, and exome library preparation was performed with the Ion Torrent AmpliSeq RDY Exome Kit. Functional studies were based on the identified mutation. RESULTS: Using WES 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 5 months of age of severe PLE. 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: The PLVAP p. Arg358* mutation resulted in the loss of PLVAP expression with subsequent deletion of the diaphragms of endothelial fenestrae, which led to plasma protein extravasation, PLE, and ultimately death.
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