Pediatric Nephrology, University of Heidelberg Children's Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Pediatr Nephrol. 2009 Dec;24(12):2361-8. doi: 10.1007/s00467-009-1287-6. Epub 2009 Aug 14.
Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.
人类先天性肾和尿路异常（CAKUT）是儿童慢性肾衰竭（CRF）的主要原因。这些疾病包括肾发育不全、发育不良、发育不良或双肾、和/或输尿管畸形。最近的研究表明，几个基因（包括 BMP4）的突变与遗传性肾脏发育疾病有关。我们以前在五个儿科 CAKUT 患者中发现了 BMP4 中的三个错义突变（S91C、T116S、N150K）。随后，我们在细胞表达系统中对这些 BMP4 突变进行了研究，这里我们提供了功能数据，证明了 Bmp4 突变体的信使 RNA（mRNA）丰度较低，这表明突变体可能对其自身 mRNA 表达和/或稳定性产生负反馈。此外，我们描述了由 S91C-BMP4 突变诱导的替代蛋白复合物的形成，这导致核周内质网（ER）积累和 Bmp4 的溶酶体降解增强。这项工作进一步支持了 BMP4 突变在人类肾脏发育异常中的作用。
