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摘要:
目的 探讨1例维吾尔族Gitelman综合征(Gitelman's syndrome, GS)患者的临床表现及其分子生物学基础。 方法 详细收集患者的临床资料、生化检查及影像学检查结果, 抽取外周静脉血, 提取基因组DNA, 聚合酶链反应(poly-merase chain reaction, PCR)扩增SLC12A3基因的26个外显子及其与内含子的交界区, 测序确定突变情况。 结果 患者临床表现、实验室检查和影像学检查符合GS诊断。基因突变分析显示, 患者SLC12A3基因cDNA序列的第1964位鸟嘌呤G纯合突变为腺嘌呤A(c.1964 G>A), 造成第655位氨基酸由精氨酸改变为组氨酸(p.Arg655His), 该突变位于SLC12A3的第16外显子。 结论 通过SLC12A3基因突变分析, 从分子遗传学方面证实1例维吾尔族患者GS的诊断。临床上持续低血钾、肾脏失钾、代谢性碱中毒、血压正常或偏低、低尿钙的患者应考虑该疾病诊断, 基因分析有助于确诊。 -
关键词:
- Gitelman综合征 /
- 低钾血症 /
- SLC12A3基因 /
- 噻嗪类敏感的钠氯共转运蛋白 /
- 基因突变
Abstract:Objective To analyze the clinical manifestations and molecular basis of a Uyghur patient with Gitelman's syndrome (GS). Methods Clinical features, laboratory data, and imaging results of this patient were collected. Genomic DNA was extracted from leukocytes of peripheral blood of the patient. Twenty-six exons of the GS gene and their boundaries with introns were amplified by polymerase chain reaction (PCR). The mutations of the SLC12A3 gene were identified by direct sequencing. Results GS was diagnosed based on comprehensive consideration of clinical presentations, laboratory test results, and imaging findings. Gene mutation test revealed a nucleotide substitution of adenine for guanine at the position 1964 of cDNA sequence of SLC12A3 gene (c.1964 G>A), which caused a missense mutation of arginine to histidine at codon 655 (p.Arg655His). It occurred at the 16th exon of SLC12A3. Conclusions SLC12A3 gene mutation analysis confirms the diagnosis of GS in this Uyghur patient from the aspect of molecular genetics. GS should be suspected in patients with per-sisting hypokalemia, renal potassium loss, metabolic alkalosis, normal or low-than-normal blood pressure, andhypocalcuria. Genetic analysis of SLC12A3 may be helpful to confirm the diagnosis. -
表 1 SLC12A3基因扩增引物
外显子 上游引物序列 下游引物序列 退火温度(℃) PCR产物长度(bp) 1 CAGACTCAGAAGAGCCACTCC CATGGCACAGATGACAGAACTG 55 640 2 AGCAGCTCAACACCCAGTG GTCAGAGCTGAGCCTGGATG 55 360 3 GGACTTGTCGTTTGGCCTTG ACAGGATTCAGGCAAGCTGG 60 210 4 CGCATGGTGAATGAGTAGGCA GTCCTGTTCCCAGGATTAGG 55 230 5 AGCCAACCGACTCATCTGGT TGAAGTCAGGCAGAGCAGCA 55 290 6 ACATCGTCCTAGCAGAGTGCA TCCACGTGACCACCTCCATG 60 266 7 GCTTCCCAGAGAGGTAGAAC TCCCAGTGTCCACACAATGG 55 260 8 CCATTGTGTGGACACTGGGA GCAGGATTCTGCTCATAGCC 52 323 9 GCTGCCTAATGTCCTCCGT AGCCCAGCTCTCCCTGTTGT 60 290 10 GCTGGAAGAGGACAGAGTAAG CAAACTTCCAGGCCTGCAAGG 60 220 11 GGAATGAAGTGCCACAGATGG CCTATTGTGCCTCTAGCCCAG 60 245 12 AGACACCAGGACCCAGGTTG TGAGGAGACAGGAGAAGAGC 55 340 13 AGGTTGAGACTGACTGAGCCT TTGAGAGGTGACCTTGGGCT 60 360 14 CCTAGAAAGAGGCTCGACTG GTGGCTTAGAGGTCGAGACA 60 420 15 GATTCCTAACTCTGCTCTCACC TCAGGTGACAGGTCTAGGCT 60 133 16 AAGCATGTAGGGTCATGCTGG AGGCATGAGCCACCATGCCT 60 265 17 GTTGAATCTCAGGCTGGAGG CATCACACCATTGCACTCCAG 60 375 18 CAGCACATCTGGAGACATCAG AAGTGAGCTTCCTGCCTCAG 55 270 19 ACTCTAGATATCTGGTCTCCTG TCTAGAACTTTCTGGGAGTGG 55 207 20 CTCAGACAAGGAGAGCCTGTG ACCTGTCCTCGACCAAGTTC 60 210 21 CACATCACAGCACTGAGCGT CCTTTGAGAGCAGGCCAGGA 60 350 22 GCAGGAACTCACATAGTGCTC GGTGGAGCTAAGATGACACTG 60 240 23 GAATCGAGATTGCACCACTG ACCCTTGCTCCTAGTCTACC 60 285 24 AATGGCAGTGTCCGATGGGT GAGCTCAAGACATGCAGGACA 55 343 25 GCCACAGAATGCTTCTTGGAG TTCCTAGGGGAAGGCTTGG 40 408 26 GACGGTAAACAGACTCGCTG GACAGGGATGTCAAAGCCTG 55 365 
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[1] Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter[J]. Nat Genet, 1996, 12:24-30. doi: 10.1038/ng0196-24 [2] Al Shibli A, Narchi H. Bartter and Gitelman syndromes:Spectrum of clinical manifestations caused by different mutations[J]. World J Methodol, 2015, 5:55-61. doi: 10.5662/wjm.v5.i2.55 [3] Wang L, Dong C, Xi YG, et al. Thiazide-sensitive Na+-Cl- cotransporter:genetic polymorphisms and human diseases[J]. Acta Biochim Biophys Sin (Shanghai), 2015, 47:325-334. doi: 10.1093/abbs/gmv020 [4] Jiang L, Chen C, Yuan T, et al. Clinical severity of Gitelman syndrome determined by serum magnesium[J]. Am J Nephrol, 2014, 39:357-366. doi: 10.1159/000360773 [5] Li C, Zhou X, Han W, et al. Identification of two novel mutations in SLC12A3 gene in two Chinese pedigrees with Gitelman syndrome and review of literature[J]. Clin Endocrinol (Oxf), 2015, doi: 10.1111/cen.12820. [6] Luo J, Yang X, Liang J, et al. A pedigree analysis of two homozygous mutant Gitelman syndrome cases[J]. Endocr J, 2015, 62:29-36. doi: 10.1507/endocrj.EJ14-0289 [7] Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome[J]. Nephron Physiol, 2008, 108:29-36. doi: 10.1159/000117815 -
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