Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex.
Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia duri...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3527294?pdf=render |
| _version_ | 1811230557765369856 |
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| author | Simon Wilkins Ke Wei Zhang Istiak Mahfuz Renaud Quantin Nancy D'Cruz John Hutson Michael Ee Darius Bagli Karen Aitken Fion Nga-Yin Fong Patrick Kwok-Shing Ng Stephen Kwok-Wing Tsui Wendy Yin-Wan Fung Tahmina Banu Atul Thakre Kaid Johar Enrique Jaureguizar Long Li Wei Cheng |
| author_facet | Simon Wilkins Ke Wei Zhang Istiak Mahfuz Renaud Quantin Nancy D'Cruz John Hutson Michael Ee Darius Bagli Karen Aitken Fion Nga-Yin Fong Patrick Kwok-Shing Ng Stephen Kwok-Wing Tsui Wendy Yin-Wan Fung Tahmina Banu Atul Thakre Kaid Johar Enrique Jaureguizar Long Li Wei Cheng |
| author_sort | Simon Wilkins |
| collection | DOAJ |
| description | Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63(-/-) mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC. |
| first_indexed | 2024-04-12T10:30:25Z |
| format | Article |
| id | doaj.art-68628a7bdeb242bbb2efb5f3d0677b3d |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T10:30:25Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-68628a7bdeb242bbb2efb5f3d0677b3d2022-12-22T03:36:52ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042012-01-01812e100307010.1371/journal.pgen.1003070Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex.Simon WilkinsKe Wei ZhangIstiak MahfuzRenaud QuantinNancy D'CruzJohn HutsonMichael EeDarius BagliKaren AitkenFion Nga-Yin FongPatrick Kwok-Shing NgStephen Kwok-Wing TsuiWendy Yin-Wan FungTahmina BanuAtul ThakreKaid JoharEnrique JaureguizarLong LiWei ChengBladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian development. It plays a role in bladder development. We have previously shown that p63(-/-) mouse embryos developed a bladder exstrophy phenotype identical to human BEEC. We hypothesised that TP63 is involved in human BEEC pathogenesis. RNA was extracted from BEEC foreskin specimens and, as in mice, ΔNp63 was the predominant p63 isoform. ΔNp63 expression in the foreskin and bladder epithelium of BEEC patients was reduced. DNA was sequenced from 163 BEEC patients and 285 ethnicity-matched controls. No exon mutations were detected. Sequencing of the ΔNp63 promoter showed 7 single nucleotide polymorphisms and 4 insertion/deletion (indel) polymorphisms. Indel polymorphisms were associated with an increased risk of BEEC. Significantly the sites of indel polymorphisms differed between Caucasian and non-Caucasian populations. A 12-base-pair deletion was associated with an increased risk with only Caucasian patients (p = 0.0052 Odds Ratio (OR) = 18.33), whereas a 4-base-pair insertion was only associated with non-Caucasian patients (p = 0.0259 OR = 4.583). We found a consistent and statistically significant reduction in transcriptional efficiencies of the promoter sequences containing indel polymorphisms in luciferase assays. These findings suggest that indel polymorphisms of the ΔNp63 promoter lead to a reduction in p63 expression, which could lead to BEEC.http://europepmc.org/articles/PMC3527294?pdf=render |
| spellingShingle | Simon Wilkins Ke Wei Zhang Istiak Mahfuz Renaud Quantin Nancy D'Cruz John Hutson Michael Ee Darius Bagli Karen Aitken Fion Nga-Yin Fong Patrick Kwok-Shing Ng Stephen Kwok-Wing Tsui Wendy Yin-Wan Fung Tahmina Banu Atul Thakre Kaid Johar Enrique Jaureguizar Long Li Wei Cheng Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. PLoS Genetics |
| title | Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. |
| title_full | Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. |
| title_fullStr | Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. |
| title_full_unstemmed | Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. |
| title_short | Insertion/deletion polymorphisms in the ΔNp63 promoter are a risk factor for bladder exstrophy epispadias complex. |
| title_sort | insertion deletion polymorphisms in the δnp63 promoter are a risk factor for bladder exstrophy epispadias complex |
| url | http://europepmc.org/articles/PMC3527294?pdf=render |
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