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
- plasmalemma vesicle-associated protein
Statistics from Altmetric.com
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.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.