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

Abstract

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.

LIM homeodomain transcription factor Isl1 affects urethral epithelium differentiation and apoptosis via Shh

“…There are many factors that cause urethral hypoplasia, including environment, diet, and heredity factors. Several studies have detected significant changes in Isl1 in human urethral hypoplasia samples compared to the normal sample by sequencing 42,60 . Draaken et al 42 reported that Isl1 DNA was significantly decreased in BEEC patients, suggesting that Isl1 plays a role in BEEC.…”

Congenital Disorders of the Human Urinary Tract: Recent Insights From Genetic and Molecular Studies

“…The prevalence has been measured as 2.1 per 100,000 births, with a positive correlation with maternal age (15). Genetic association studies have implicated variation in the ISL1 locus in classic bladder extrophy, yet pathogenic variants in the ISL1 coding region have not been proven (101, 102). Another idea is that the association with the ISL1 locus indicates functional variation of a non-coding genomic region that affects ISL1 expression but this hypothesis has yet to be proven (103).…”

“…Another idea is that the association with the ISL1 locus indicates functional variation of a non-coding genomic region that affects ISL1 expression but this hypothesis has yet to be proven (103). ISL1 is a transcription factor known to be expressed in the region of the forming mouse bladder (102). Mutant Isl1 mice have an epispadias-like phenotype, and in normal development the encoded transcription factor induces bone morphogenetic factor 4 (BMP4) mediated remodeling of mesenchymal cells (104).…”

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

“…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, ).…”