中国家族性肾性糖尿SGLT2基因突变分析及表型和基因型相关性研究  

Analysis on the mutation of SLC5A2 gene in Chinese patients with familial renal glucosuria and investigation on the association of genotype and phenotype

作　　者：王晓慧[1] 赵向忠[2] 李春梅[1] 袁鹰[3] 邵乐平[1] 

机构地区：[1]青岛大学医学院附属医院肾脏科,266003 [2]青岛大学医学院中心实验室,266003 [3]青岛大学医学院内分泌科,266003

出　　处：《中华肾脏病杂志》2016年第1期1-8,共8页Chinese Journal of Nephrology

基　　金：国家自然科学基金面上项目（81170653）

摘　　要：目的总结中国7个家系的家族性肾性糖尿（FRG）患者的临床特点，验证和分析FRG患者及其亲属Na＋-葡萄糖协同转运蛋白2（SGLT2）基因突变位点，探讨FRG患者的基因型和表型的相关关系。方法检测7个家系FRG先证者及其一级亲属共23名家庭成员（其中14例患者）24h尿糖及血尿生化指标。PCR法扩增SGLT2全部编码区及其侧翼序列，用直接测序法分析SGLT2基因突变位点。结果SGLT2基因测序结果发现5个新的基因突变。包括4个错义突变：8号外显子第335位丝氨酸突变为甘氨酸（p．S335G，c．1003A〉G）；11号外显子第448位谷氨酰胺突变为精氨酸（p．Q448R，c．1343A〉G）；474位的丙氨酸突变为脯氨酸（p．A474P，c．1420G〉C）；13号外显子第580位甘氨酸突变为天冬氨酸（p-G580D，c．1739G〉A）；1个7号内含子缺失突变c．886（-10_-31）del，该突变经迷你基因（pSPL3外显子捕获质粒）验证为剪切突变。14例患者c．886（-10_-31）del的突变等位基因频率为43％（12／28）。纯合或复合杂合突变的患者表现为中重度肾性糖尿，杂合突变的患者表现为轻中度肾性糖尿，符合共显性遗传特点。结论我们发现5种新的突变基因型与中国人群家族性肾性糖尿相关，c．886（一10_一31）del可能为中国人群的高频突变基因。Objective To describe and analyze the clinical characters of patients with FRG from 7 Chinese families. Then analyze and identify their mutations in SGLT2 gene, and explore the association of genotype and phenotype. Methods Quantitative test for 24-hour urine glucose and other laboratory tests were carried out among 7 probands （14 patients in all） and their family members from 7 pedigrees （totaling 23 subjects）. All coding regions, including intronexon boundaries, were analyzed using PCR followed by direct sequence analysis. Results Five novel mutations in SLC5A2 gene were identified in this investigation, including four missense mutations （A Serine to Glycine at position 335 （c.1003A 〉 G, p.S335G）, a Glutamine to Arginine at position 448 （c.1343A〉 G, p. Q448R）, an alanine to proline at position 474 （p.A474P, c.1420G 〉 C） and a glycine to aspartic acid at position 580 （c.1739G 〉 A, p.G580D） and a deletion in intron 7 （c.886（-10_-31）del）. By the minigene studies using the pSPL3 plasmids, we confirmed the deletion c.886（-10._-31）del as a splicing mutation.In this study, the mutation c.886（-10_-31）del accounted for about 43% of the total alleles （12/28）. These patients with compound heterozygous or homozygous mutations manifested middle degree or severe glycosuria （Quantitative test for 24-hour urine glucose： 10.56-50.68 g/1.73 m2）, however those with heterozygous variants presented with mild to moderate glycosuria （Quantitative test for 24-hour urine glucose ≤2.45 g/1.73 mS）. This fits co-dominant inheritance pattern. Conclusions Five novel mutations which may be related to FRG are found in this study, and c.886（-10-31） del may be a high frequency mutation in Chinese patients.

关 键 词：肾性糖尿 家族性 SGLT2基因 突变 基因型 

分 类 号：R692[医药卫生—泌尿科学]