Trochen Nadja, Ganapathipillai Santhirasekaran, Ferrari Paolo, Frey Brigitte M, Frey Felix J
Division of Nephrology and Hypertension, University Hospital, Berne, Switzerland.
Nephrol Dial Transplant. 2004 Oct;19(10):2499-504. doi: 10.1093/ndt/gfh417. Epub 2004 Aug 10.
The serum- and glucocorticoid-regulated kinase (SGK1) gene is an important mediator of aldosterone action, regulating the expression of the renal epithelial Na(+) channel. In renal failure, blood pressure (BP) is markedly salt-dependent and increases with decreasing renal function. Mutations of the SGK1 gene affecting phosphorylation could be responsible for salt-mediated increases in BP and hypertension-related progression to end-stage renal disease (ESRD).
The SGK1 gene was analysed for mutations in the exons 4, 5, 8 and 10-12, because of potential phosphorylation sites, in 591 subjects, including 311 ESRD patients (either dialysis or transplanted). In addition, an intron 6 single-nucleotide polymorphism (SNP) described previously was also investigated in this study. Genotyping was performed either by using a strategy based on single strand conformation polymorphism analysis of polymerase chain reaction (PCR) products and subsequent direct sequencing of identified gel shift variants or by using high throughput 5' nuclease allelic discrimination assay.
Two SNPs in coding regions of SGK1 potentially influencing the phosphorylation of Sgk1 were identified. Both SNPs were synonymous. The prevalence of the first variant, a previously reported SNP at codon 240 in exon 8, did not differ between ESRD patients (16.3%) and controls (15.7%). There was no association between the SNP in exon 8 and either BP within the control population or progression of renal disease in the ESRD population. The second SNP at codon 398 in exon 12 was identified in one patient only. Intron 6 and exon 8 SNPs were in strong linkage disequilibrium, but did not show any association with either BP or renal diseases.
Based on statistical analysis homozygosity for nonconservative mutations in the coding region of the SGK1 gene is estimated at < 1/300 000 when a white Caucasian population is considered, arguing against an important role of mutations of this coding region in hypertension and hypertension-associated progression of renal disease.
血清和糖皮质激素调节激酶（SGK1）基因是醛固酮作用的重要介质，可调节肾上皮钠通道的表达。在肾衰竭时，血压（BP）明显依赖于盐，并随肾功能下降而升高。影响磷酸化的SGK1基因突变可能是盐介导的血压升高及高血压相关的终末期肾病（ESRD）进展的原因。
由于存在潜在的磷酸化位点，对591名受试者（包括311例ESRD患者，均为透析患者或移植患者）的SGK1基因的第4、5、8和10至12外显子进行了突变分析。此外，本研究还对先前描述的内含子6单核苷酸多态性（SNP）进行了研究。基因分型采用基于聚合酶链反应（PCR）产物的单链构象多态性分析及随后对鉴定出的凝胶迁移变体进行直接测序的策略，或采用高通量5'核酸酶等位基因鉴别分析。
在SGK1的编码区鉴定出两个可能影响Sgk1磷酸化的SNP。这两个SNP均为同义突变。第一个变体是外显子8中密码子240处先前报道的SNP，其在ESRD患者（16.3%）和对照组（15.7%）中的患病率无差异。外显子8中的SNP与对照组人群的血压或ESRD人群的肾病进展均无关联。仅在一名患者中鉴定出了外显子12中密码子398处的第二个SNP。内含子6和外显子8的SNP处于强连锁不平衡状态，但与血压或肾病均无关联。
基于统计分析，当考虑白种人群体时，SGK1基因编码区非保守突变的纯合率估计<1/300 000，这表明该编码区突变在高血压及高血压相关的肾病进展中不起重要作用。
