PUBLICATION
WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish
- Authors
- Baranowska Körberg, I., Hofmeister, W., Markljung, E., Cao, J., Nilsson, D., Ludwig, M., Draaken, M., Holmdahl, G., Barker, G., Reutter, H., Vukojević, V., Clementson Kockum, C., Lundin, J., Lindstrand, A., Nordenskjöld, A.
- ID
- ZDB-PUB-150625-6
- Date
- 2015
- Source
- Human molecular genetics 24(18): 5069-78 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Mice
- Models, Molecular
- Phenotype
- Gene Expression
- Open Reading Frames
- Genetic Association Studies
- Mutation
- Protein Transport
- Bladder Exstrophy/genetics*
- Animals
- High-Throughput Nucleotide Sequencing
- Penetrance
- Humans
- Zebrafish/embryology*
- Zebrafish/genetics*
- Cloaca/embryology*
- Cloaca/metabolism*
- Protein Conformation
- RNA, Messenger/genetics
- NIH 3T3 Cells
- Wnt3 Protein/chemistry
- Wnt3 Protein/genetics*
- Wnt3 Protein/metabolism
- Polymorphism, Single Nucleotide
- Gene Knockdown Techniques
- PubMed
- 26105184 Full text @ Hum. Mol. Genet.
Citation
Baranowska Körberg, I., Hofmeister, W., Markljung, E., Cao, J., Nilsson, D., Ludwig, M., Draaken, M., Holmdahl, G., Barker, G., Reutter, H., Vukojević, V., Clementson Kockum, C., Lundin, J., Lindstrand, A., Nordenskjöld, A. (2015) WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish. Human molecular genetics. 24(18):5069-78.
Abstract
Bladder exstrophy, a severe congenital urological malformation when a child is born with an open urinary bladder, is the most common form of bladder exstrophy-epispadias complex (BEEC) with an incidence of 1:30.000 children of Caucasian descent. Recent studies suggest that WNT genes may contribute to the etiology of bladder exstrophy. Here, we evaluated WNT pathway genes in 20 bladder exstrophy patients using massively parallel sequencing. In total 13 variants were identified in WNT3, WNT6, WNT7A, WNT8B, WNT10A, WNT11, WNT16, FZD5, LRP1 and LRP10 genes and predicted as potentially disease causing, of which seven variants were novel. One variant, identified in a patient with a de novo nonsynonymous substitution in WNT3 (p.Cys91Arg), was further evaluated in zebrafish. Knock down of wnt3 in zebrafish showed cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen. Our study suggests that the function of the WNT3 p.Cys91Arg variant was altered, since RNA overexpression of mutant Wnt3 RNA does not result in embryonic lethality as seen with wild type WNT3 mRNA. Finally, we also mutation screened the WNT3 gene further in 410 DNA samples from BEEC cases and identified one additional mutation c.638G>A (p.Gly213Asp), which was paternally inherited. In aggregate our data support the involvement of WNT pathway genes in BEEC and suggest that WNT3 in itself is a rare cause of BEEC.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping