Possible Role of WT1 in a Human Fetus with Evolving Bronchial Atresia, Pulmonary Malformation and Renal Agenesis

Abstract

The association of peripheral bronchial atresia and congenital pulmonary airway malformation (CPAM) has recently been recognised, but the pathology of the lesions evolving together has not been described. We present autopsy findings in a 20 week fetus showing areas of peripheral bronchial destruction and airway malformation consistent with developing CPAM in the right lung supporting a causal relationship between these lesions. This fetus also had congenital heart defect, bilateral renal agenesis and syndactyly. We identified another fetus from our autopsy files, with bilateral renal agenesis, similar right sided pulmonary malformation and cardiac defects. Similar bilateral renal agenesis and defects of the heart and lungs are found in wt1(-/-) mice and we have investigated the expression of WT1 in these fetuses. We hypothesise that the cardiac, liver, renal and possibly lung lesions in these two cases may arise due to mesenchymal defects consequent to WT1 misexpression and discuss evidence for this from the scientific literature. We used immunoperoxidase stains to analyse WT1 expression in autopsy hepatic tissue in both fetuses. We also investigated the expression of α-smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells/myofibroblasts, and desmin in hepatic mesenchyme and compare these findings with control fetuses, without congenital malformations. We found reduced WT1 expression in hepatic mesothelium in both fetuses with malformations. There was also increased expression of α-SMA in liver perisinusoidal cells, as seen in the wt1(-/-) mouse model. We therefore propose that abnormality of WT1 signalling may be an underlying factor, as WT1 is expressed in coelomic lining cells from which mesenchyme is derived in many organs.

The development of hepatic stellate cells in normal and abnormal human fetuses - an immunohistochemical study

“…MLPA investigations in a renal agenesis fetus with abnormal WT1 expression in liver mesothelium suggested that wt1 was not mutated in this fetus (Loo et al. 2012a ). The wt1 −/− mouse model shows reduced liver size, abnormal stellate cell development and diaphragmatic defects (Ijpenberg et al.…”

Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart

“…Monozygotic twins with congenital nephrotic syndrome caused by a WT1 mutation have been reported to have died due to sepsis and extensive thrombosis of central venous system and sepsis and sudden heart failure at ages 23 weeks/13.5 months, respectively [ 112 ]. WT1 misexpression has been reported in autopsy findings from two human fetuses, displaying congenital pulmonary airway malformation, bilateral renal agenesis, and congenital heart defects [ 113 ]. Shortly after, re-evaluation of autopsy data from fourteen additional fetuses with combined renal agenesis and cardiac anomalies revealed abnormalities of Wt1 expression, mostly in liver mesenchymal cells.…”

Mesothelium and Malignant Mesothelioma

“…Loss of WT1 results in reduced cardiomyocyte mass, pericardial hemorrhage, thinning of the myocardial wall, and embryonic lethality [49,51]. Mutations in the WT1 gene have also been associated with pulmonary dysplasia [52], hypoplastic lung malformation [53], diaphragmatic hernia [54], decreased mesothelial cell entry into the lung [18], and mesothelioma [55]. In addition, WT1 plays a crucial role in liver development.…”