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Published on: August 15, 2019
Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans
Samir Bouasker1, Nisha Patel2, Rebecca Greenlees3
1Research Center, University Hospital Centre Sainte-Justine, Montreal H3T 1C5, Québec, Canada.
Insights
Genetic variants in WNT7B cause PDAC syndrome, a disorder characterized by pulmonary hypoplasia and other defects. This discovery implicates WNT-β-catenin signaling in human development.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Medicine
Background:
- PDAC syndrome is a rare disorder characterized by Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects.
- Previous genetic studies linked PDAC syndrome to variants in RARB and STRA6.
- The genetic cause for PDAC syndrome in patients without these known variants remained unidentified.
Purpose of the Study:
- To identify the genetic basis of PDAC syndrome in patients negative for RARB and STRA6 pathogenic variants.
- To functionally validate candidate gene variants associated with PDAC syndrome.
Main Methods:
- Whole exome sequencing was performed on patients with unexplained PDAC syndrome.
- Functional assays, including a WNT signaling luciferase assay, were used to validate candidate variants.
- Zebrafish (wnt7bb mutant) models were employed to assess conserved WNT7B function in organ development.
Main Results:
- Bi-allelic variants in WNT7B were identified in fetuses with PDAC syndrome from two unrelated families.
- Identified WNT7B variants (p.(Arg98*), p.(Tyr75*), and p.(Gly188Ser)) were shown to be deleterious through functional assays.
- Mutant zebrafish (wnt7bb) exhibited swimbladder defects, suggesting conserved WNT7B function in lung homolog development.
Conclusions:
- Defective WNT7B function is a cause of a PDAC syndrome subtype characterized by lung hypoplasia.
- The WNT-β-catenin pathway plays a crucial role in the development of multiple human organs, including lungs, trachea, eyes, heart, and kidneys.
Background:
Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder.
Methods:
We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.
Results:
We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures.
Conclusion:
Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-β-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.
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