20例Gitelman综合征患者中高发突变的基因型与表型关系
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摘要
目的对收集的枣庄地区和青岛地区20例Gitelman综合征患者进行致病基因SLC12A3的突变基因型及表型进行分析,探讨其中高发突变的基因型与表型的关系。方法本研究组选取2013至2016年在青岛大学附属医院和枣庄矿业集团中心医院住院治疗的20例经基因测序确诊的Gitelman综合征患者。其中男性13例,女性7例,平均年龄(33±12)岁。收集20例患者的一般临床资料和相关的实验室检查结果,包括性别、发病年龄、症状、体征、血压、血钾、血镁、血HCO-3、血浆肾素活性、血浆醛固酮、24h尿Ca2+/Cr。查找20例经基因确诊患者的突变基因型。将不同突变基因型的患者的一般临床资料和实验室检查结果进行相应的分析比较。对50例非相关的健康者进行相关的基因测序,查找有无SLCl2A3基因上的突变。结果 20例患者中均存在SLC12A3的突变,共发现了15个相关的突变位点,其中错义突变9个(Cys430Gly、Leu571Pro、Thr60Met、Asp486Asn、Glu429Lys、Ala264Gly、Ser283Thr、Thr163Met、Arg913Gln),缺失突变5个(1384delG、346-353delACTGATGG、2883-2884delAG、1740delC、2877-2878delAG),插入突变1个(997insCys);其中杂合突变2例,纯合突变1例,复合杂合突变17例;有8例患者发现了Ala264Gly的突变,发生率约为20. 5%。Ala264GLy携带者的发病年龄、四肢乏力、手足搐搦、多尿等症状的发生与携带其他突变的患者无显著性差异,实验室检查方面Ala264Gly携带者的血钾、血镁、血HCO-3、血浆肾素活性、血浆醛固酮、24h尿Ca2+/Cr与携带其他突变的患者差异无统计学意义。结论 ALa264Gly突变可能是本研究中两个地区的高频突变,但Ala264Gly导致的临床表型无特异性。
Objective To analyze the mutation genotype and phenotype of pathogenic gene SLC12 A3 in 20 patients with Gitelman syndrome collected from Zaozhuang,and investigate the relationship between genotype and phenotype of the high mutation. Methods The enrolled included 20 patients with Gitelman syndrome confirmed by gene sequencing from 2013 to 2016 in the Affiliated Hospital of Qingdao University and Central Hospital of Zaozhuang Mining Group. There were 13 males and 7 females,with an average age of( 33 ± 12) years. The mutant genotype,clinical manifestation,serum potassium,serum magnesium,blood bicarbonate,plasma angiotensin,aldosterone,and 24 h urinary calcium/creatinine were analyzed in 20 patients. The mutant genotype was found in 20 patients. The general clinical data and laboratory test results of different genotypes were correspondingly analyzed and compared. Gene sequencing was performed on 50 unrelated healthy subjects to find if there were any mutations in the SLCl2 A3 gene. Results Mutations in the SLCl2 A3 gene were found in 20 patients. A total of 15 related mutations were identified,including 9 missense mutations( Cys430 Gly,Leu571 Pro,Thr60 Met,Asp486 Asn,Glu429 Lys,Ala264 Gly,Ser283 Thr,Thr163 Met,Arg913 Gln),5 deletion mutations( 1384 delG,346-353 delACTGATGG,2883-2884 delAG,1740 delC,2877-2878 delAG),1 insertion mutation( 997 insCys). Heterozygous mutations were found in 2 cases,homozygous mutations in 1 case,and heterozygous heterozygous mutations in 17 cases. The Ala264 gly mutation was found in 8 cases,and the incidence was 20. 5%. There was no significant difference in the clinical manifestations between Ala264 Gly carriers and patients with other mutations. There was no significant difference in serum potassium,serum magnesium,blood bicarbonate,plasma angiotensin,aldosterone,and 24-h urinary calcium/creatinine between Ala264 Gly carriers and patients with other mutations. Conclusions The Ala264 Gly mutation may be a high frequency mutation in two regions of this study. The clinical phenotype caused by high incidence mutation Ala264 Gly was not specific.
Objective To analyze the mutation genotype and phenotype of pathogenic gene SLC12 A3 in 20 patients with Gitelman syndrome collected from Zaozhuang,and investigate the relationship between genotype and phenotype of the high mutation. Methods The enrolled included 20 patients with Gitelman syndrome confirmed by gene sequencing from 2013 to 2016 in the Affiliated Hospital of Qingdao University and Central Hospital of Zaozhuang Mining Group. There were 13 males and 7 females,with an average age of( 33 ± 12) years. The mutant genotype,clinical manifestation,serum potassium,serum magnesium,blood bicarbonate,plasma angiotensin,aldosterone,and 24 h urinary calcium/creatinine were analyzed in 20 patients. The mutant genotype was found in 20 patients. The general clinical data and laboratory test results of different genotypes were correspondingly analyzed and compared. Gene sequencing was performed on 50 unrelated healthy subjects to find if there were any mutations in the SLCl2 A3 gene. Results Mutations in the SLCl2 A3 gene were found in 20 patients. A total of 15 related mutations were identified,including 9 missense mutations( Cys430 Gly,Leu571 Pro,Thr60 Met,Asp486 Asn,Glu429 Lys,Ala264 Gly,Ser283 Thr,Thr163 Met,Arg913 Gln),5 deletion mutations( 1384 delG,346-353 delACTGATGG,2883-2884 delAG,1740 delC,2877-2878 delAG),1 insertion mutation( 997 insCys). Heterozygous mutations were found in 2 cases,homozygous mutations in 1 case,and heterozygous heterozygous mutations in 17 cases. The Ala264 gly mutation was found in 8 cases,and the incidence was 20. 5%. There was no significant difference in the clinical manifestations between Ala264 Gly carriers and patients with other mutations. There was no significant difference in serum potassium,serum magnesium,blood bicarbonate,plasma angiotensin,aldosterone,and 24-h urinary calcium/creatinine between Ala264 Gly carriers and patients with other mutations. Conclusions The Ala264 Gly mutation may be a high frequency mutation in two regions of this study. The clinical phenotype caused by high incidence mutation Ala264 Gly was not specific.
引文
[1]Simon DB,Nelson-Williams,Bia MJ,et al.Gitelman’s variaant of Bartter’s Syndrome,inherited hypokalaemic alkalosis,is caused by mutations in the thiazide-sensitive Na-Cl contransporter[J].Nal Genet,1996,12(1):24-30.
[2]Bettinelli A,Bianchetti MG,Girardin E,et al.Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis:Bartter and gitelman syndromes[J].J Pediatr,1992,120(1):38-43.
[3]Lin SH,Shiang JC,Huang CC.Phenotypeand genotype analysis in Chinese patients with Gitelman’s syndrome[J].J Clin Endocrinol Metab,2005,90(5):2500-2507.
[4]Lin SH,Cheng NL,Hsu YJ.Intra familial phenol type variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter[J].Am J Kidney Dis,2004,43(2):304-312.
[5]Chen Z,Vaughn DA,Fanestil DD.Influence of gender on renal thiazide diuretic receptor density and response[J].J Am Sec Nephrol,1994,5:1112-1119.
[6]Jeck N,Schlingmann KP,Reinalter SC,et al.Salt handling in the distal nephron:Lessons learned from inherited human disorders[J].Am J Physiol Regul Integr Comp Physiol,2005,288:R782-R795.
[7]邵乐平,逯静茹,郎艳平,等.中国Gitelman综合征患者的基因型、表型分析及随访研究[J].中华内分泌代谢杂志,2017,33(1):40-46.
[8]Wong KC,Wang Z.Prevalence of type 2 diabetes mellitus of Chinese population in Mainland China,Hong Kong,and Taiwan[J].Diabetes Res Clin Pract,2006,73(2):126-134.
[9]Huo X,Gao L,Guo L,et al.RISK of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China:Across sectional study[J].Lancet Diabetes Endocrinol,2016,4(2):115-124.
[10]Reissinger A,Ludwig M,Utsch B,et al.Novel NCCT gene mutations as a cause of Gitelman syndrome and a systematic review of mutant and polymorphic NCCT alleles[J].Kidney Blood Press Res,2002,25:354-362.
[11]Miao Z,Gao Y,Bindels RJ,et al.Coexistence of normotensive primary aldosteronism in two patients with Gitelman’s syndrome and novel thiazide-sensitive Na-Cl cotransporter mutations[J].Eur JEndoccrinol,2009,161(2):275-283.
[12]Ji W,Foo JN,O Roak BJ,et al.Rare independent mutations in renal salt handling genes contribute to blood pressure variation[J].Nat Genet,2008,40(5):592-599.
[13]Colussi G,Bettinelli A,Tedeschi S,et al.A thiazide test for the diagnosis of renal tubular hypokalemic disorders[J].Clin J Am Soc Nephrol,2007,2(3):454-460.
[14]秦岭,邵乐平,任红,等.中国人Gitelman综合征高发突变的基因型和表型特征.肾脏病与透析肾移植杂志[J],2008,8:331-334.
[15]王艳,韩正斌,邵乐平,等.10例Gitelman综合征患者SLC12A3基因的检测[J].肾脏病与透析肾移植杂志,2015,24(5):419-424.
[16]Coto E,Rodriguez J,Jeck N,et al,A new mutation(intron 9+1G>T)in the SLC12A3 gene is linked to Gitelman syndrome in Gypsis[J].Kidney Int,2004,65:25-29.
[17]Riveira-Munoz E,Chang Q,Godefroid N.Transcriptional and functional analyses of SLC12A3 mutations:New clues for the pathogenesis of Gitelman syndrom[J].J Am Soc Nephrol,2007,18:1271-1283.
[18]邵乐平,任红,王伟铭,等.Gitelman综合征SLC12A3基因突变研究[J],中华肾脏病杂志,2007:23(6):351-356.
[2]Bettinelli A,Bianchetti MG,Girardin E,et al.Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis:Bartter and gitelman syndromes[J].J Pediatr,1992,120(1):38-43.
[3]Lin SH,Shiang JC,Huang CC.Phenotypeand genotype analysis in Chinese patients with Gitelman’s syndrome[J].J Clin Endocrinol Metab,2005,90(5):2500-2507.
[4]Lin SH,Cheng NL,Hsu YJ.Intra familial phenol type variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter[J].Am J Kidney Dis,2004,43(2):304-312.
[5]Chen Z,Vaughn DA,Fanestil DD.Influence of gender on renal thiazide diuretic receptor density and response[J].J Am Sec Nephrol,1994,5:1112-1119.
[6]Jeck N,Schlingmann KP,Reinalter SC,et al.Salt handling in the distal nephron:Lessons learned from inherited human disorders[J].Am J Physiol Regul Integr Comp Physiol,2005,288:R782-R795.
[7]邵乐平,逯静茹,郎艳平,等.中国Gitelman综合征患者的基因型、表型分析及随访研究[J].中华内分泌代谢杂志,2017,33(1):40-46.
[8]Wong KC,Wang Z.Prevalence of type 2 diabetes mellitus of Chinese population in Mainland China,Hong Kong,and Taiwan[J].Diabetes Res Clin Pract,2006,73(2):126-134.
[9]Huo X,Gao L,Guo L,et al.RISK of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China:Across sectional study[J].Lancet Diabetes Endocrinol,2016,4(2):115-124.
[10]Reissinger A,Ludwig M,Utsch B,et al.Novel NCCT gene mutations as a cause of Gitelman syndrome and a systematic review of mutant and polymorphic NCCT alleles[J].Kidney Blood Press Res,2002,25:354-362.
[11]Miao Z,Gao Y,Bindels RJ,et al.Coexistence of normotensive primary aldosteronism in two patients with Gitelman’s syndrome and novel thiazide-sensitive Na-Cl cotransporter mutations[J].Eur JEndoccrinol,2009,161(2):275-283.
[12]Ji W,Foo JN,O Roak BJ,et al.Rare independent mutations in renal salt handling genes contribute to blood pressure variation[J].Nat Genet,2008,40(5):592-599.
[13]Colussi G,Bettinelli A,Tedeschi S,et al.A thiazide test for the diagnosis of renal tubular hypokalemic disorders[J].Clin J Am Soc Nephrol,2007,2(3):454-460.
[14]秦岭,邵乐平,任红,等.中国人Gitelman综合征高发突变的基因型和表型特征.肾脏病与透析肾移植杂志[J],2008,8:331-334.
[15]王艳,韩正斌,邵乐平,等.10例Gitelman综合征患者SLC12A3基因的检测[J].肾脏病与透析肾移植杂志,2015,24(5):419-424.
[16]Coto E,Rodriguez J,Jeck N,et al,A new mutation(intron 9+1G>T)in the SLC12A3 gene is linked to Gitelman syndrome in Gypsis[J].Kidney Int,2004,65:25-29.
[17]Riveira-Munoz E,Chang Q,Godefroid N.Transcriptional and functional analyses of SLC12A3 mutations:New clues for the pathogenesis of Gitelman syndrom[J].J Am Soc Nephrol,2007,18:1271-1283.
[18]邵乐平,任红,王伟铭,等.Gitelman综合征SLC12A3基因突变研究[J],中华肾脏病杂志,2007:23(6):351-356.