WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish

Körberg, Izabella Baranowska; Hofmeister, Wolfgang; Markljung, Ellen; Cao, Jia; Nilsson, Daniel; Ludwig, Michael; Draaken, Markus; Holmdahl, Gundela; Barker, Gillian; Reutter, Heiko; Vukojević, Vladana; Kockum, Christina Clementson; Lundin, Johanna; Wedell, Anna; Nordenskjöld, Agneta

doi:10.1093/hmg/ddv225

Cited by 23 publications

(25 citation statements)

References 37 publications

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“… 7–9 Recently, a novel, potentially disease-causing variant in the WNT3 gene was identified. 10 Overexpression of this human WNT3 containing the p.Cys91Arg variant in zebrafish caused cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

et al. 2018

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Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

et al. 2018

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“…Increasing amount of information by genome‐wide association methods and robust advances of next‐generation sequencing (NGS) provide more information on causative genes for defective urogenital/reproductive organ formation . They include Wnt3 and Wnt9b .…”

Section: Suggested Signals For the Body Wall And Associated Organ Formentioning

confidence: 99%

Epispadias and the associated embryopathies: genetic and developmental basis

et al. 2016

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The abnormalities in the urogenital organs are frequently observed as human developmental diseases. Among such diseases, the defects in the upper part of external genitalia are rather rare named epispadias. The cleft in the dorsal part of external genitalia often reaches to the urethra. In general, the urogenital abnormalities accompany defects in the adjacent tissues and organs. The ventral body wall and bladder can also be affected in the patients with dorsal defects of the external genitalia. Therefore, such multiple malformations are often classified as bladder exstrophy and epispadias complex (BEEC). Because of the lower frequency of such birth defects and their early embryonic development, animal models are required to analyze the pathogenic mechanisms and the functions of responsible genes. Mutant mouse analyses on various signal cascades for external genitalia and body wall development are increasingly performed. The genetic interactions between growth factors such as bone morphogenetic proteins (Bmp) and transcription factors such as Msx1/2 and Isl1 have been suggested to play roles for such organogenesis. The significance of epithelial–mesenchymal interaction (EMI) is suggested during development. In this review, we describe on such local interactions and developmental regulators. We also introduce some mutant mouse models displaying external genitalia‐body wall abnormalities.

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“…From studies both on chromosomal as well as base‐pair level several regions, genes and gene‐pathways have been suggested to be associated with BEEC susceptibility (Arkani et al, ; Baranowska Korberg et al, ; Draaken et al, ; Reutter et al, ; von Lowtzow et al, ). For example, a 900 kb microduplication on chromosome 19p13.12 was identified in one patient (Draaken et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…In total 13 variants were identified in WNT ‐pathway genes of which seven variants were novel. One de novo variant in the WNT3 (OMIM 165330) gene was further evaluated in zebrafish supporting an altered function of the mutant (Baranowska Korberg et al, ). Also, Wnt3 and Wnt9b (OMIM 602864) have been shown to be expressed in genital tubercle in mouse embryos in a period that corresponds to bladder development in humans.…”

Section: Introductionmentioning

confidence: 99%

Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene

Lundin

Markljung

Körberg

et al. 2019

Molec Gen & Gen Med

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Background The bladder exstrophy‐epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods We performed array comparative genomic hybridization (array‐CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.

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WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish

Cited by 23 publications

References 37 publications

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort

Epispadias and the associated embryopathies: genetic and developmental basis

Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene

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