Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia.
Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia.
复制标题
DOI：
10.1016/j.jcmgh.2015.05.001
复制
发表时间：
2015-07
影响因子：
7.2
通讯作者：
Muise AM
中科院分区：
文献类型：
--
作者：
Elkadri A;Thoeni C;Deharvengt SJ;Murchie R;Guo C;Stavropoulos JD;Marshall CR;Wales P;Bandsma R;Cutz E;Roifman CM;Chitayat D;Avitzur Y;Stan RV;Muise AM
在非常年幼的儿童中观察到的严重肠道疾病通常是单基因缺陷的结果。我们使用全外显子组测序（WES）来检查一名患有不同严重形式的蛋白丢失性肠病（PLE）的患者的遗传学，该患者的特征是低蛋白血症、低白蛋白血症和高胆固醇血症。WES在Centre for Applied Genomics，Hospital for Sick Children，多伦多，加拿大进行，并且外显子组文库制备用Ion Torrent AmpliSeq RDY外显子组试剂盒进行。功能研究是基于所确定的突变。使用WES，我们在一名婴儿的PLVAP（质膜囊泡相关蛋白）基因中发现了一个纯合无义突变（1072 C>T; p.Arg358*），该婴儿来自于5个月大死于严重PLE的近亲父母。功能研究确定，突变的PLVAP mRNA和蛋白质在患者活检组织中不表达，推测继发于无义介导的mRNA衰变。病理分析表明，PLVAP的丧失导致内皮有孔隔膜的破坏。PLVAP p.Arg358* 突变导致PLVAP表达丧失，随后内皮窗隔缺失，导致血浆蛋白外渗、PLE和最终死亡。
Severe intestinal diseases observed in very young children are often the result of monogenic defects. We used whole-exome sequencing (WES) to examine genetics in a patient with a distinct severe form of protein-losing enteropathy (PLE) characterized by hypoproteinemia, hypoalbuminemia, and hypertriglyceridemia. WES was performed at the Centre for Applied Genomics, Hospital for Sick Children, Toronto, Canada, and exome library preparation was performed with the Ion Torrent AmpliSeq RDY Exome Kit. Functional studies were based on the identified mutation. Using WES we identified a homozygous nonsense mutation (1072C>T; p.Arg358*) in the PLVAP (plasmalemma vesicle-associated protein) gene in an infant from consanguineous parents who died at 5 months of age of severe PLE. Functional studies determined that the mutated PLVAP mRNA and protein were not expressed in the patient biopsy tissues, presumably secondary to nonsense-mediated mRNA decay. Pathological analysis showed that the loss of PLVAP resulted in disruption of endothelial fenestrated diaphragms. The PLVAP p.Arg358* mutation resulted in the loss of PLVAP expression with subsequent deletion of the diaphragms of endothelial fenestrae, which led to plasma protein extravasation, PLE, and ultimately death.