Studying Pentalogy of Cantrell in Humans and Mice

坎特雷尔五联症(POC)在人类中的发病率估计为每100万活产中有1-5.5例。这种综合征通常是致命的，包括：1)胸骨不融合，伴随着细胞凋亡的减少，从而导致胎儿出生时心脏在胸壁外。(2)横隔部突出，使腹部器官伸入胸腔。3)由于腹壁变弱导致的含有腹部器官的脐膨出，4)心包缺失，5)心脏结构和瓣膜缺陷，包括室间隔缺陷和主动脉出口移位到右室。我们的实验室已经产生了非肌肉肌球蛋白IIB重链(由Myh10编码)的点突变(R709C)小鼠，它模仿人类的POC。小鼠模型的产生促使我们在人类中启动了一项临床研究，在该研究中，我们进行了全外显子组测序，以确定POC的可能遗传病因。到目前为止，在我们研究中登记的22名先证者中，有一人是胎儿病例，其余病例的年龄从登记时的1天到31岁不等。我们筛选了每个家族中与POC分离的外显子组数据中的罕见变异。来自同一个家庭的两个患病个体携带Teneurin-4基因(TENM4)的一个罕见变异，该变异高度保守，预计是有害的；另外两个亲属是杂合子，但显然没有受到影响，这表明该变异对POC表现出不完全外显。Teneurins是一个保守的跨膜蛋白家族，作为转录激活剂在细胞间信号转导中发挥作用。当作为跨膜蛋白时，分子的胞内羧基末端与肌动蛋白细胞骨架相互作用。我们目前正在研究6个新的变种，在未受影响的父母所生的POC患者中发现。为了解释结果，我们正在开发遗传和蛋白质相互作用网络，以了解POC的潜在机制(S)。我们希望通过在世界范围内招募受这种罕见疾病影响的家庭来增加识别POC的遗传病因的可能性。

The incidence of Pentalogy of Cantrell (POC) in humans is estimated at 1-5.5 per 1 million live births. The syndrome is often fatal and includes: 1) a sternum that is not fused associated with a decrease in apoptosis, thus causing the fetus to be born with the heart external to the thoracic wall. 2) herniation of the diaphragm allowing the abdominal organs to protrude into the thoracic cavity. 3) an omphalocele containing abdominal organs due to a weakened abdominal wall, 4) a missing pericardium and 5) structural and valvular defects in the heart including a ventricular septal defect and displacement of the aorta outlet to the right ventricle. Our laboratory has generated mice with a point mutation (R709C) in the non-muscle myosin IIB heavy chain (encoded by Myh10) which mimic the human POC. Generation of the mouse model prompted us to initiate a clinical study in humans in which we conducted whole-exome sequencing to determine a possible genetic etiology for POC. Of the twenty-two probands enrolled in our study to date, one is a fetal case, and the remaining cases range from 1 day to 31 years of age at enrollment. We filtered for rare variants in the exome data that segregated with POC in each family. Two affected individuals from the same family carry a rare variant in the teneurin-4 gene (TENM4) that is highly conserved and predicted to be deleterious; two additional relatives were heterozygous but apparently unaffected, suggesting that the variant exhibits incomplete penetrance for POC. Teneurins are a conserved family of transmembrane proteins that play a role in intercellular signaling as transcriptional activators. When serving as a transmembrane protein the intracellular carboxyl terminal end of the molecule interacts with the actin cytoskeleton. We are currently investigating 6 de novo variants, identified in individuals with POC born to unaffected parents. To interpret the results, we are developing genetic and protein-interaction networks in order to understand the mechanism(s) underlying POC. We hope to increase the likelihood of identifying genetic etiologies for POC through worldwide recruitment of families affected by this rare disorder.