RT Journal Article SR Electronic T1 Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2018-105299 DO 10.1136/jmedgenet-2018-105299 A1 Alina Kurolap A1 Orly Eshach-Adiv A1 Claudia Gonzaga-Jauregui A1 Katya Dolnikov A1 Adi Mory A1 Tamar Paperna A1 Tova Hershkovitz A1 John D Overton A1 Marielle Kaplan A1 Fabian Glaser A1 Yaniv Zohar A1 Alan R Shuldiner A1 Gidon Berger A1 Hagit N Baris YR 2018 UL http://jmg.bmj.com/content/early/2018/06/06/jmedgenet-2018-105299.abstract 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>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.