Arkani Samara, Cao Jia, Lundin Johanna, Nilsson Daniel, Källman Thomas, Barker Gillian, Holmdahl Gundela, Clementsson Kockum Christina, Matsson Hans, Nordenskjöld Agneta
Department of Women's and Children's Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Hum Genome Var. 2018 Mar 29;5:18009. doi: 10.1038/hgv.2018.9. eCollection 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 variants were identified. RNA sequencing revealed 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 gene in 125 Swedish BEEC patients, indicating that variation in the gene is not a common genetic mechanism of BEEC development in the Swedish population.
膀胱外翻是一种先天性膀胱闭合缺陷，对发病率有深远影响。尽管这种畸形通常是散发性的，但亲属中复发风险增加、单卵双胞胎中更高的一致性率以及几种相关的染色体畸变都支持其存在遗传背景。最近，在两项不同的研究中，该基因被提出作为膀胱外翻和尿道上裂复合体（BEEC）发育的候选基因。在我们的研究中，我们使用桑格测序和阵列比较基因组杂交分析，对125名瑞典患者的DNA中的该基因遗传变异进行了筛查。此外，我们评估了在胚胎和胎儿第5至10周期间人膀胱RNA中相对于肺组织（第9周）的该基因表达。总共鉴定出21个单核苷酸变异，包括一个潜在的新错义变异，c.137C>G p.(Ala46Gly)，替换了一个保守氨基酸。这个变异是从一位未受影响的母亲那里遗传来的。未鉴定出结构变异。RNA测序揭示了在人膀胱发育的关键时间框架内该基因的mRNA表达。总之，我们在125名瑞典BEEC患者中未检测到该基因的任何已知或可能的致病变异，这表明该基因的变异不是瑞典人群中BEEC发育的常见遗传机制。
