McGill University Department of Human Genetics', Montreal Children's Hospital Research Institute, Montreal, Canada.
Hum Mol Genet. 2011 Nov 1;20(21):4167-74. doi: 10.1093/hmg/ddr341. Epub 2011 Aug 5.
Human nephrons are formed during fetal life through an interaction between the branching ureteric bud and progenitor cells. The wide variation in final nephron number has been attributed to allelic variants of genes regulating ureteric bud arborization. Here, we hypothesize that dysfunctional variants of the Odd-Skipped Related 1 (OSR1) gene which compromise the renal progenitor cell pool might also limit newborn kidney size and function. We show that OSR1 is expressed in human mesenchymal stem cells, the blastemal component of Wilms tumors and CD24+/CD133+ progenitor cells isolated from the mature kidney. We identified an OSR1(rs12329305(T)) allele in 6% of normal Caucasians which alters an exon2 splice enhancer. This variant is predicted to reduce spliceosome-binding affinity and stability of the OSR1 mRNA. In cultured cells, the OSR1(rs12329305)(T) allele produced no identifiable transcript. Normal Caucasian newborns from Montreal with the OSR1(rs12329305)(T) allele had kidney volume 11.8% smaller (P= 0.006) and cord blood cystatin C levels 12.6% higher (P = 0.005) than those with wild-type genotype. Effects of the OSR1(rs12329305)(T) allele are additive with genes that alter ureteric bud branching. Kidney volume was reduced more in newborns bearing both RET(rs1800860)(A) and OSR1(rs12329305)(T) alleles (22%, P= 0.0008) and cystatin C was increased by 17% (P= 0.006) versus newborns with wild-type alleles. Although only two subjects had PAX2(rs11599825)(A) and OSR1(rs12329305)(T) alleles, kidney size was reduced by 27% and cystatin C was increased by 14% versus wild-types (P= NS).
人类肾单位是在胎儿期通过分支输尿管芽和祖细胞之间的相互作用形成的。最终肾单位数量的广泛变化归因于调节输尿管芽分支的基因的等位变体。在这里，我们假设Odd-Skipped Related 1（OSR1）基因的功能失调变体可能会损害肾祖细胞池，也可能限制新生儿的肾脏大小和功能。我们表明，OSR1 在人类间充质干细胞、Wilms 肿瘤的胚性成分和从成熟肾脏中分离的 CD24+/CD133+祖细胞中表达。我们在 6%的正常白种人中发现了一个 OSR1(rs12329305(T))等位基因，该等位基因改变了外显子 2 的剪接增强子。这种变体预计会降低剪接体结合亲和力和 OSR1 mRNA 的稳定性。在培养的细胞中，OSR1(rs12329305)(T)等位基因没有产生可识别的转录物。来自蒙特利尔的具有 OSR1(rs12329305)(T)等位基因的正常白种人新生儿的肾脏体积小 11.8%（P=0.006），脐带血胱抑素 C 水平高 12.6%（P=0.005）比具有野生型基因型的新生儿。OSR1(rs12329305)(T)等位基因的作用与改变输尿管芽分支的基因是累加的。携带 RET(rs1800860)(A)和 OSR1(rs12329305)(T)等位基因的新生儿的肾脏体积减少更多（22%，P=0.0008），胱抑素 C 增加 17%（P=0.006），而具有野生型等位基因的新生儿。尽管只有两个受试者具有 PAX2(rs11599825)(A)和 OSR1(rs12329305)(T)等位基因，但与野生型相比，肾脏大小减少 27%，胱抑素 C 增加 14%（P=NS）。
