Porteous S, Torban E, Cho N P, Cunliffe H, Chua L, McNoe L, Ward T, Souza C, Gus P, Giugliani R, Sato T, Yun K, Favor J, Sicotte M, Goodyer P, Eccles M
Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Hum Mol Genet. 2000 Jan 1;9(1):1-11. doi: 10.1093/hmg/9.1.1.
PAX2 mutations cause renal-coloboma syndrome (RCS), a rare multi-system developmental abnormality involving optic nerve colobomas and renal abnormalities. End-stage renal failure is common in RCS, but the mechanism by which PAX2 mutations lead to renal failure is unknown. PAX2 is a member of a family of developmental genes containing a highly conserved 'paired box' DNA-binding domain, and encodes a transcription factor expressed primarily during fetal development in the central nervous system, eye, ear and urogenital tract. Presently, the role of PAX2 during kidney development is poorly understood. To gain insight into the cause of renal abnormalities in patients with PAX2 mutations, kidney anomalies were analyzed in patients with RCS, including a large Brazilian kindred in whom a new PAX2 mutation was identified. In a total of 29 patients, renal hypoplasia was the most common congenital renal abnormality. To determine the direct effects of PAX2 mutations on kidney development fetal kidneys of mice carrying a Pax2 (1Neu)mutation were examined. At E15, heterozygous mutant kidneys were approximately 60% of the size of wild-type littermates, and the number of nephrons was strikingly reduced. Heterozygous 1Neu mice showed increased apoptotic cell death during fetal kidney development, but the increased apoptosis was not associated with random stochastic inactivation of Pax2 expression in mutant kidneys; Pax2 was shown to be biallelically expressed during kidney development. These findings support the notion that heterozygous mutations of PAX2 are associated with increased apoptosis and reduced branching of the ureteric bud, due to reduced PAX2 dosage during a critical window in kidney development.
PAX2突变会导致肾-眼裂综合征（RCS），这是一种罕见的多系统发育异常疾病，涉及视神经裂和肾脏异常。终末期肾衰竭在RCS中很常见，但PAX2突变导致肾衰竭的机制尚不清楚。PAX2是一个发育基因家族的成员，含有一个高度保守的“配对盒”DNA结合结构域，编码一种主要在胎儿发育期间于中枢神经系统、眼睛、耳朵和泌尿生殖道表达的转录因子。目前，人们对PAX2在肾脏发育过程中的作用了解甚少。为了深入了解PAX2突变患者肾脏异常的原因，对RCS患者的肾脏异常进行了分析，包括一个发现了新的PAX2突变的大型巴西家族。在总共29名患者中，肾发育不全是最常见的先天性肾脏异常。为了确定PAX2突变对肾脏发育的直接影响，研究了携带Pax2（1Neu）突变的小鼠的胎儿肾脏。在胚胎第15天，杂合突变体肾脏的大小约为野生型同窝小鼠的60%，肾单位数量显著减少。杂合1Neu小鼠在胎儿肾脏发育过程中凋亡细胞死亡增加，但凋亡增加与突变体肾脏中Pax2表达的随机失活无关；在肾脏发育过程中，Pax2呈双等位基因表达。这些发现支持了这样一种观点，即在肾脏发育的关键时期，由于PAX2剂量减少，PAX2的杂合突变与输尿管芽凋亡增加和分支减少有关。
