PUBLICATION
Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans
- Authors
- Bouasker, S., Patel, N., Greenlees, R., Wellesley, D., Fares Taie, L., Almontashiri, N.A., Baptista, J., Alghamdi, M.A., Boissel, S., Martinovic, J., Prokudin, I., Holden, S., Mudhar, H.S., Riley, L.G., Nassif, C., Attie-Bitach, T., Miguet, M., Delous, M., Ernest, S., Plaisancié, J., Calvas, P., Rozet, J.M., Khan, A.O., Hamdan, F.F., Jamieson, R.V., Alkuraya, F.S., Michaud, J.L., Chassaing, N.
- ID
- ZDB-PUB-220707-3
- Date
- 2022
- Source
- Journal of Medical Genetics 60(3): 294-300 (Journal)
- Registered Authors
- Delous, Marion, Ernest, Sylvain
- Keywords
- human genetics
- MeSH Terms
-
- Animals
- Base Sequence
- Exome
- Humans
- Lung*/pathology
- Mammals/metabolism
- Wnt Proteins/metabolism
- Wnt Signaling Pathway
- Zebrafish*
- PubMed
- 35790350 Full text @ J. Med. Genet.
Citation
Bouasker, S., Patel, N., Greenlees, R., Wellesley, D., Fares Taie, L., Almontashiri, N.A., Baptista, J., Alghamdi, M.A., Boissel, S., Martinovic, J., Prokudin, I., Holden, S., Mudhar, H.S., Riley, L.G., Nassif, C., Attie-Bitach, T., Miguet, M., Delous, M., Ernest, S., Plaisancié, J., Calvas, P., Rozet, J.M., Khan, A.O., Hamdan, F.F., Jamieson, R.V., Alkuraya, F.S., Michaud, J.L., Chassaing, N. (2022) Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans. Journal of Medical Genetics. 60(3):294-300.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping