结石症家系的基因型和表型分析  

Analysis of Genotype and Phenotype in the Calculi Family Lineage

作　　者：梁文沛 何永华 蒲金赟 马雪晴 邵盼盼 仇丽茹[1,2] LIANG Wenpei;HE Yonghua;PU Jinyun;MA Xueqing;SHAO Panpan;QIU Liru(Department of Pediatrics Nephrology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Hubei Provincial Key Laboratory for Rare Endocrine and Metabolic Diseases in Children,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院儿童肾脏专科,武汉430030 [2]儿童遗传代谢内分泌罕见病湖北省重点实验室,武汉430030

出　　处：《医药导报》2025年第4期589-595,共7页Herald of Medicine

基　　金：湖北省卫生健康委面上项目(WJ2023M004);北京医学奖励基金会项目(YXJL-2023-0866-0329)。

摘　　要：目的通过结石症家系的分子遗传学分析,探讨其发病机制以及基因型和表型的关联。方法回顾性分析华中科技大学同济医学院附属同济医院收治的一个结石症家系,收集患儿和部分家系成员的临床资料和外周血,进行全外显子组测序,对候选变异进行Sanger测序验证。结果4代共38例家系成员中10例患有结石症,第2代二号(Ⅱ-2)、第3代二号(Ⅲ-2)、第3代四号(Ⅲ-4)成员患复发性多发性肾结石和胆结石,第2代六号(Ⅱ-6)、第2代十三号(Ⅱ-13)、第3代五号(Ⅲ-5)成员仅患有复发性多发性肾结石,第1代二号(Ⅰ-2)、第2代四号(Ⅱ-4)、第2代八号(Ⅱ-8)、第2代十一号(Ⅱ-11)成员仅患有胆结石,余家系成员无肾脏和胆囊受累表现。Ⅱ-2成员2018年诊断为终末期肾脏病5期、高血压3级、胆结石,尿氨基酸高效液相色谱分析提示尿胱氨酸浓度升高,既往患复发性多发性肾结石和反复泌尿道感染30余年,有多次输尿管镜取石术史。基因分析结果显示Ⅱ-2、Ⅲ-2、Ⅲ-4、Ⅲ-5、Ⅳ-1成员均携带溶质载体家族3成员1(solute carrier family 3 member 1,SLC3A1)基因第10号外显子c.1889G>A(p.Gly630Asp)杂合变异,第3代一号(Ⅲ-1)、第4代二号(Ⅳ-2)成员为野生型,该突变存在家系共分离现象。结论SLC3A1基因c.1889G>A杂合变异可能是该家系多成员患结石症的遗传学病因。复发性多发性肾结石和(或)胆结石需要高度关注遗传学病因。建议对结石症家系以及早发结石症患者进行基因分析。Objective Through molecular genetics analysis of a calculi family lineage,this study aims to explore its pathogenesis and the association between genotypes and phenotypes.Methods A retrospective analysis was conducted on a calculi family lineage admitted to Tongji Hospital,affiliated with Tongji Medical College,Huazhong University of Science and Technology.Clinical data and peripheral blood samples of the affected children and some family members were collected.Whole exome sequencing was performed,followed by Sanger sequencing to validate the candidate variants.Results Among the 38 family members across four generations,10 members were diagnosed with calculi disease.The second generation,member 2(Ⅱ-2),third generation,member 2(Ⅲ-2),and third generation,member 4(Ⅲ-4)suffered from recurrent multiple kidney stones and gallstones.The second generation,member 6(Ⅱ-6),second generation,member 13(Ⅱ-13),and third generation,member 5(Ⅲ-5)had recurrent multiple kidney stones alone,while first generation,member 2(Ⅰ-2),second generation,member 4(Ⅱ-4),second generation,member 8(Ⅱ-8),and second generation,member 11(Ⅱ-11)only had gallstones.No other family members exhibited any signs of kidney or gallbladder involvement.II-2 was diagnosed in 2018 with end-stage renal disease stage 5,grade 3 hypertension and gallstones,urinary amino acid high-performance liquid chromatography analysis indicated elevated urinary cystine.This member had a history of recurrent multiple kidney stones and recurrent urinary tract infections for over 30 years,with multiple histories of ureteroscopic stone removal.Genetic analysis revealed thatⅡ-2,Ⅲ-2,Ⅲ-4,Ⅲ-5 andⅣ-1 all carry a heterozygous mutation in exon 10 of the solute carrier family 3 member 1(SLC3A1)gene,c.1889G>A(p.Gly630Asp).The third generation,member 1(Ⅲ-1),and fourth generation,member 2(Ⅳ-2),are wild type.This mutation shows a phenomenon of family co-segregation.Conclusions The heterozygous mutation of SLC3A1 gene,c.1889G>A,may be the genetic cause of calculi

关 键 词：肾结石 胆结石 胱氨酸尿症 SLC3A1基因 全外显子组测序 

分 类 号：R726.9[医药卫生—儿科] R725.7[医药卫生—临床医学]