Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

Broekaert, Ilse; Becker, Kerstin; Gottschalk, Ingo; Körber, Friederike; Dötsch, Jörg; Thiele, Holger; Altmüller, Janine; Nürnberg, Peter; Hünseler, Christoph; Çırak, Sebahattin

doi:10.1136/jmedgenet-2018-105262

Cited by 20 publications

(20 citation statements)

References 17 publications

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“…Disease onset in the proband (III-1) was in early adulthood, whereas patient IV-2 had childhood onset of PLE. Moreover, patient IV-2 had severe hypertriglyceridaemia, with plasma concentrations 16-fold higher than normal range, similar to the first reported PLVAP -null patient,7 while the proband had normal serum triglycerides; triglyceride levels were not reported in Broekaert et al 8 This phenotypic variability suggests the presence of other modifying factors. Review of the proband’s WES results revealed that he carries a heterozygous nonsense variant in CETP (NM_000078.2:c.544C>T;p.Gln182*), which encodes the cholesteryl ester transfer protein, while patient IV-2 is wild type.…”

Section: Discussionsupporting

confidence: 76%

“…(B) Sequence chromatogram of the c.101T>C variant in a homozygous patient and heterozygous parent. (C) Structure of the PLVAP gene (top) and PLVAP (PV-1) protein (bottom), denoting the location of reported variants: the c.101T>C;p.Leu34Pro missense variant identified in this study, and the nonsense pathogenic variants described previously by Elkadri et al 7 and Broekaert et al 8 both occurring in the third exon and truncating the protein in the second coiled-coil domain. TM, transmembrane; PRR, proline-rich region.…”

Section: Methodssupporting

confidence: 73%

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Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

et al. 2018

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Section: Discussionsupporting

confidence: 76%

Section: Methodssupporting

confidence: 73%

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

et al. 2018

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“…Endothelial diaphragms are ~40‐80 nm subcellular structures critical for life . They occur in endothelial cells (EC) of capillaries and venules in select vascular beds (reviewed in).…”

Section: Introductionmentioning

confidence: 99%

“…PLVAP knockdown in human or mouse cells results in endothelial diaphragms disappearance. Similarly, PLVAP deletion in mice or nonsense mutations in humans lead to no diaphragm formation. The in vivo loss of diaphragms results in failure of endothelial barrier function.…”

Section: Introductionmentioning

confidence: 99%

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1‐dependent and p38, JNK and PI3K/Akt‐independent manner

Hamilton

Tse

Stan

2018

J Cellular Molecular Medi

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Endothelial diaphragms are subcellular structures critical for mammalian survival with poorly understood biogenesis. Plasmalemma vesicle associated protein (PLVAP) is the only known diaphragm component and is necessary for diaphragm formation. Very little is known about PLVAP regulation. Phorbol esters (PMA) are known to induce de novo PLVAP expression and diaphragm formation. We show that this induction relies on the de novo production of soluble factors that will act in an autocrine manner to induce PLVAP transcription and protein expression. We identified vascular endothelial growth factor‐A (VEGF‐A) signalling through VEGFR2 as a necessary but not sufficient downstream event as VEGF‐A inhibition with antibodies and siRNA or pharmacological inhibition of VEGFR2 only partially inhibit PLVAP upregulation. In terms of downstream pathways, inhibition of MEK1/Erk1/2 MAP kinase blocked PLVAP upregulation, whereas inhibition of p38 and JNK MAP kinases or PI3K and Akt had no effect on PMA‐induced PLVAP expression. In conclusion, we show that VEGF‐A along with other secreted proteins act synergistically to up‐regulate PLVAP in MEK1/Erk1/2 dependent manner, bringing us one step further into understanding the genesis of the essential structures that are endothelial diaphragms.

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“…Exome sequencing of the index patient was performed using the Illumina HiSeq (Illumina, San Diego, CA, USA) 2,000 sequencing instrument with 2 Â 76 bp as described earlier. 11 Exome sequencing resulted in > 81 million of mapped unique sequences with a mean coverage of 70, that is, Â20 coverage for 92.1% of the target sequences. The Cologne Center for Genomics VARBANK pipeline v.2.24 (Cologne Center for Genomics, Cologne) (https://varbank.ccg.uni-koeln.de/) was used for read mapping, variant calling, and variant filtering.…”

Section: Clinical Case Presentationmentioning

confidence: 99%

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

et al. 2019

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Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported.We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE.We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism.

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Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

Abstract: Our findings validate mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.

Cited by 20 publications

References 17 publications

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1‐dependent and p38, JNK and PI3K/Akt‐independent manner

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

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