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Genotype-phenotype correlations
Short report
Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype
  1. Alina Kurolap1,2,
  2. Orly Eshach-Adiv2,3,
  3. Claudia Gonzaga-Jauregui4,
  4. Katya Dolnikov5,
  5. Adi Mory1,
  6. Tamar Paperna1,
  7. Tova Hershkovitz1,
  8. John D Overton4,
  9. Marielle Kaplan2,6,
  10. Fabian Glaser7,
  11. Yaniv Zohar8,
  12. Alan R Shuldiner4,
  13. Gidon Berger2,5,
  14. Hagit N Baris1,2
  1. 1 The Genetics Institute, Rambam Health Care Campus, Haifa, Israel
  2. 2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel
  3. 3 Pediatric Gastroenterology and Pediatrics B, Rambam Health Care Campus, Haifa, Israel
  4. 4 Regeneron Genetics Center, Tarrytown, New York, USA
  5. 5 Department of Internal Medicine B, Rambam Health Care Campus, Haifa, Israel
  6. 6 Laboratory of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel
  7. 7 Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion–Israel Institute of Technology, Haifa, Israel
  8. 8 Institute of Pathology, Rambam Health Care Campus, Haifa, Israel
  1. Correspondence to Dr Hagit N Baris, The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; hb_feldman{at}rambam.health.gov.il

Abstract

Background Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.

Objective To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.

Methods Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function.

Results We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.

Conclusions Biallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

  • protein-losing enteropathy
  • hypertriglyceridemia
  • plasmalemma vesicle-associated protein
  • PLVAP

https://doi.org/10.1136/jmedgenet-2018-105299

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    Footnotes

    • AK, OE-A, CG-J and KD contributed equally.

    • GB and HNB contributed equally.

    • Contributors AK and HNB collected and summarised patient data. AK, CG-J, AM, TP, JDO and ARS participated in exome sequencing, bioinformatic data analysis and variant cosegregation analysis. OE-A, KD, TH and GB followed and treated the patients. MK contributed to interpretation of laboratory analyses. FG performed the computational analyses of the missense variant effect on the protein; YZ performed electron microscopy and immunohistochemistry on patient intestinal biopsies. AK, TP and HNB drafted the manuscript. All coauthors critically reviewed and approved the final version of the submitted manuscript.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval The Helsinki Ethics Committee of Rambam Health Care Campus.

    • Provenance and peer review Not commissioned; externally peer reviewed.