Genetic Mutation Causes Lethal Condition in Infants

Protein losing enteropathy (PLE) is a condition of the gastrointestinal tract that results in loss of protein from the body, and often leads to severe abdominal swelling, malnutrition and early death in affected infants.

Whole-exome sequencing has been used to identify a nonsense mutation in the plasmalemma vesicle-associated protein gene that results in a distinct severe form of PLE characterized by hyperproteinemia, hypoalbuminemia, and hypertriglyceridemia.


Scientists at the Hospital for Sick Children (Toronto, ON, Canada) obtained samples from a patient with the PLVAP p.Arg358* mutation on two occasions during endoscopic investigation for severe PLE. Control samples from the duodenum or colon were obtained from patients who were undergoing evaluation of gastrointestinal symptoms, among whom the endoscopic, histologic, and follow-up clinical impressions were normal.

Whole-exome sequencing was performed and the exome library preparation was performed using the Ion Torrent AmpliSeq RDY Exome Kit (Life Technologies; Carlsbad, CA, USA) and DNA quantified by Qubit DNA HS or BR assay (Life Technologies). The library was purified with Agencourt Ampure XT beads (Agencourt Bioscience; Beverly, MA, USA). Libraries were quantified by quantitative polymerase chain reaction (PCR) and sequenced on an Ion Torrent Proton Sequencer using a PI chip V2. The investigators used a variety of techniques for their study including flow cytometry read on a FACSCalibur (BD Biosciences; San Jose, CA, USA), confocal microscopy, histology and immunofluorescence.

The defect caused by mutations in PLVAP was due to increased leakage from small blood vessels rather than active loss from the cells lining the intestines. This finding is different from most cases of enteropathy, including the Microvillus Inclusion Disease and Congenital Tufting Enteropathy, which affect young children. In these latter conditions, genetic abnormalities cause cellular abnormalities primarily affecting intestinal epithelial tissue structure and function.

Abdul Elkadri, the lead study author, said, “These findings come at a critical time in medical science; the recent promise of gene therapy may make targeted correction of PLVAP mutations possible. In the meantime, we can use these findings to develop more rapid diagnostic strategies to screen infants for this genetic mutation and prevent severe complications at an early stage of the disease.” The study was published in the July 2015 issue of the journal Cellular and Molecular Gastroenterology and Hepatology.

Related Links:
Hospital for Sick Children
Life Technologies
Agencourt Bioscience