Laboratory of Histomorphology and Molecular Biology of the Kidney, Division of Nephrology, Department of Medical and Surgical Sciences, University Hospital of Padua, Via Giustiniani, 2. 35128 Padua, Italy.
Clin J Am Soc Nephrol. 2010 Jul;5(7):1205-10. doi: 10.2215/CJN.07551009. Epub 2010 May 6.
Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development.
Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.-45G>C and c.-27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[-45G>C; -27+18G>A] complex allele, and the others had the c.-27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene.
This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.
海绵状肾（MSK）是一种罕见的肾病，其特征为集合管囊状异常、肾钙质沉着症、肾结石和肾小管功能障碍。其与各种畸形和家族聚集病例的关联支持遗传因素参与的观点，但迄今为止尚未进行任何遗传研究。据推测，MSK 是由于关键发育基因异常导致输尿管芽/后肾间充质界面中断所致。
设计、环境、参与者和测量：通过直接对胶质细胞源性神经营养因子（GDNF）基因和转染重排（RET）基因的所有外显子和外显子-内含子边界进行 DNA 测序，对 55 例明显散发的 MSK 患者进行了分析，这两个基因在肾脏发育中起主要作用。
在 MSK 病例群体中发现了两种杂合性新变异：GDNF{ENST00000344622}:c.-45G>C 和 c.-27+18G>A，位于配对盒 2 转录因子的假定结合域内。总体而言，有 8 例患者存在这些变异：4 例患者携带 c.[-45G>C; -27+18G>A]复合等位基因，其余患者仅携带 c.-27+18G>A。病例对照研究表明，这两个等位基因与 MSK 显著相关。在 8 例病例中，有 5 例为家族性病例，等位基因变异与疾病在显性遗传模式中紧密相关。患者未发现 RET 基因的突变。
这是首例在 MSK 患者中发现 GDNF 基因突变的报告，并提示该基因在某些 MSK 病例的发病机制中起作用。
