ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development (original) (raw)
Related papers
Human genome variation, 2018
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 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 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated 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 variant...
Communications Biology
Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes res...
2014
Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P 5 8.88 3 10 25 ; followup: P 5 0.0025; combined: 1.09 3 10 26 ) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P 5 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.
Genetic screening of patients with bladder exstrophy epispadias complex
2015
Bladder Exstrophy Epispadias Complex (BEEC) is a serious congenital anomaly. Babies affected are born with an exposed bladder, and leak urine continually. The high incidence among the offspring, siblings and identical twins of BEEC patients suggests a genetic etiology. We previously showed that TP63 is a candidate gene of this disorder. There are two main isoforms, TAP63 and ΔNP63, and ΔNp63 is expressed predominantly in the murine bladder epithelium. Notably, p63-/- mice developed a condition similar to BEEC. In addition, the p63-/- mutation led to an increase in apoptosis, decrease in cell proliferation and absence of smooth muscle development in the bladder. We found that ΔNP63 expression is reduced in BEEC patients’ bladders, whereas TAP63 expression is increased. Although, no mutations were found in P63 coding sequence, we did identify In/del polymorphisms in the ΔNP63 promoter that were associated with significantly increased risk of BEEC. The analysis of the TAP63 promoter re...
Genetics and the lower urinary tract
Neurourology and Urodynamics, 2010
Many complex disorders have been found to have a heritable component, including lower urinary tract dysfunction. Twin studies have indicated that genetic contributions to urinary incontinence (UI) may be as important as environmental influences. Linkage to chromosome 9 has been demonstrated in families with pelvic organ prolapse and stress UI. An increasing number of incontinence specialists are studying subjects with lower urinary tract dysfunction using single nucleotide polymorphisms, linkage analyses of siblings, and large association studies. These findings have exciting implications for future prevention and treatment of UI.
Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12
Birth Defects Research Part A: Clinical and Molecular Teratology, 2013
BACKGROUND: The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC. METHODS: Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes. RESULTS: A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ. CONCLUSIONS: The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene Birth Defects Research (Part A) 97:133-139, 2013.