PT - JOURNAL ARTICLE AU - Alina Kurolap AU - Orly Eshach-Adiv AU - Claudia Gonzaga-Jauregui AU - Katya Dolnikov AU - Adi Mory AU - Tamar Paperna AU - Tova Hershkovitz AU - John D Overton AU - Marielle Kaplan AU - Fabian Glaser AU - Yaniv Zohar AU - Alan R Shuldiner AU - Gidon Berger AU - Hagit N Baris TI - Establishing the role of <em>PLVAP</em> in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype AID - 10.1136/jmedgenet-2018-105299 DP - 2018 Jun 06 TA - Journal of Medical Genetics PG - jmedgenet-2018-105299 4099 - http://jmg.bmj.com/content/early/2018/06/06/jmedgenet-2018-105299.short 4100 - http://jmg.bmj.com/content/early/2018/06/06/jmedgenet-2018-105299.full AB - 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&gt;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.