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WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish.

Baranowska Körberg, Izabella; Hofmeister, Wolfgang; Markljung, Ellen; Cao, Jia; Nilsson, Daniel; Ludwig, Michael; Draaken, Markus; Holmdahl, Gundela; Barker, Gillian and Reutter, Heiko, et al. (2015) In Human Molecular Genetics 24(18). p.5069-5078
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... (More)
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. (Less)
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published
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Human Molecular Genetics
volume
24
issue
18
pages
5069 - 5078
publisher
Oxford University Press
external identifiers
  • pmid:26105184
  • wos:000361317200001
  • scopus:84940654910
ISSN
0964-6906
DOI
10.1093/hmg/ddv225
language
English
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yes
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0a9e7b08-9048-453a-a4ae-4d9fc4530d2c (old id 7478044)
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http://www.ncbi.nlm.nih.gov/pubmed/26105184?dopt=Abstract
date added to LUP
2015-07-10 22:03:37
date last changed
2017-02-26 03:17:16
@article{0a9e7b08-9048-453a-a4ae-4d9fc4530d2c,
  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.},
  author       = {Baranowska Körberg, Izabella and Hofmeister, Wolfgang and Markljung, Ellen and Cao, Jia and Nilsson, Daniel and Ludwig, Michael and Draaken, Markus and Holmdahl, Gundela and Barker, Gillian and Reutter, Heiko and Vukojević, Vladana and Clementson Kockum, Christina and Lundin, Johanna and Lindstrand, Anna and Nordenskjöld, Agneta},
  issn         = {0964-6906},
  language     = {eng},
  number       = {18},
  pages        = {5069--5078},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish.},
  url          = {http://dx.doi.org/10.1093/hmg/ddv225},
  volume       = {24},
  year         = {2015},
}