胱氨酸尿症（cystinuria，CSNU）是临床少见遗传病，由溶质载体家族3成员1（Solute Carrier Family3 Member 1，SLC3A1）和溶质载体家族7成员9（Solute Carrier Family 7 Member 9，SLC7A9）两个基因突变导致。CSNU患者基因突变及基因分型一直备受临床关注，本文针对CSNU相关基因SLC3A1和SLC7A9的遗传突变情况、基因型-表型相关性及近期新药研究进展作一综述。

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[1]MOUSSA M, PAPATSORIS AG, ABOU CHAKRA M,et al. Update on cystine stones: current and future conceptsin treatment [J]. Intractable Rare Dis Res, 2020, 9(2): 71-78.

[2]CLAES DJ, JACKSON E. Cystinuria: mechanisms andmanagement [J]. Pediatr Nephrol. 2012, 27(11): 2031-2038.

[3]李钧,王文营,杜源,等.儿童胱氨酸结石的诊断和治疗(附13例报告)[J].临床泌尿外科杂志, 2016, 31(11): 1012-1015.

[4]王政昊,白云金,王佳豪,等.胱氨酸结石患者的临床特点及其防治现状的研究[J].成都医学院学报, 2020, 15(2): 238-242.

[5]RHODES HL, YARRAM-SM ITH L, R ICE SJ, et al.Clinical and genetic analysis of patients with cystinuria inthe United Kingdom [J]. Clin J Am Soc Nephrol, 2015,10(7): 1235-1245.

[6]ALGHAMDI M, ALHASAN KA, TAHA ELAWAD A,et al. Diversity of Phenotype and Genetic Etiology of 23Cystinuria Saudi Patients: A Retrospective Study [J]. FrontPediatr, 2020, 8: 569389.

[7]EISNER BH, GOLDFARB DS, BAUM MA, et al.Evaluation and Medical Management of Patients with CystineNephrolithiasis: A Consensus Statement [J]. J Endourol,2020, 34(11): 1103-1110.

[8]ANDREASSEN KH, PEDERSEN KV, OSTHER SS,et al. How should patients with cystine stone disease be evaluatedand treated in the twenty-first century? [J]. U rolithiasis.2016, 44(1) 65-76.

[9]PROT-BERTOYE C, DAUDON M, TOSTIVINT I, et al.Cystinuria [J]. Nephrol Ther, 2021,17S: S100-S107.

[10] EGGERMANN T, VENGHAUS A, ZERRES K. Cystinuria:an inborn cause of urolithiasi [J]. O rphanet J Rare Dis,2012, 7: 19.

[11]王政昊,白云金,曹德宏,等.胱氨酸尿症的发病机制和基因治疗前景[J].实用医院临床杂志, 2020, 17(2): 256-258

[12] FERNÁNDEZ E, CARRASCAL M, ROUSAUD F, et al.BAT-b(0, + )AT heterodimer is the main apical reabsorptionsystem for cystine in the kidney [J]. Am J Physiol RenalPhysiol, 2002, 283(3):F540-F548.

[13] FELIUBADALÓL, ARBONÉS ML, MAÑAS S, et al.Slc7a9-deficient mice develop cystinuria non-I and cystineurolithiasis [J]. Hum Mol Genet, 2003, 12(17): 2097-2108.

[14] DI GIACOPO A, RUBIO-ALIAGA I, CANTONE A,et al. Differential cystine and dibasic amino acid handlingafter loss of function of the amino acid transporter b0, +AT (Slc7a9) in mice [J]. Am J Physiol Renal Physiol,2013, 305(12) F1645-1655.

[15] OBAID A, NASHABAT M, AL FAKEEH K, et al.Delineation of cystinuria in Saudi Arabia: A case series [J].BMC Nephrol, 2017, 18(1): 50.

[16] SARAVAKOS P, KOKKINOU V, GIANNATOS E. Cystinuria:current diagnosis and management [J]. Urology, 2014, 83(4):693-699.

[17]孙西钊,贺雷,叶章群.胱氨酸结石的病因、诊断和治疗[J].临床泌尿外科杂志, 2008, (9): 645-648.

[18] KOWALCZYK NS, ZISMAN AL. Cystinuria: Review ofa Life-long and Frustrating Disease [J]. Yale J Biol Med,2021, 94(4): 681-686.

[19]ROGERS A, KALAKISH S, DESAI RA, et al. Managementof cystinuria [J]. Urol Clin North Am, 2007, 34(3): 347-362.

[20] SAHOTA A, TISCHFIELD JA, GOLDFARB DS, et al.Cystinuria: genetic aspects, mouse models, and a new approachto therapy [J]. Urolithiasis, 2019, 47(1): 57-66.

[21] DELLO STROLOGO L, PRAS E, PONTESILLI C, et al.Comparison betweenSLC3A1andSLC7A9cystinuria patientsand carriers: a need for a new classification [J]. J Am SocNephrol, 2002, 13(10): 2547-2553.

[22] HALALSHEH OM, AL-SHEHABAT MA, AL-GHAZOMA, et al. Analysis ofSLC7A9gene mutations among Jordanianpatients with cystinuria [J]. Ann Med Surg (Lond), 2021,63: 102182.

[23] FAZAELI S, ASHOURI S, KHEIROLLAHI M, et al.A Novel Mutation inSLC7A9Gene in Cystinuria [J]. IranJ Kidney Dis, 2017, 11(2):138-141.

[24] KOULIVAND L, MOHAMMADI M, EZATPOUR B,et al. Mutation analysis ofSLC3A1andSLC7A9genes inpatients with cystinuria [J]. Urolithiasis, 2015, 43 (5): 447-453.

[25] LI C, YANG Y, ZHENG Y, et al. Genetic and ClinicalAnalyses of 13 Chinese Families With Cystine Urolithiasisand Identification of 15 Novel Pathogenic Variants inSLC3A1andSLC7A9[J]. Front Genet, 2020, 11: 74.

[26] BOTZENHART E, VESTER U, SCHMIDT C, et al.Cystinuria in children: Distribution and frequencies of mutationsin theSLC3A1andSLC7A9genes [J]. Kidney Int, 2002,62(4): 1136-1142.

[27] CHATZIKYRIAKIDOU A, LOUIZOU E, DEDOUSIS GV,et al. An overview ofSLC3A1andSLC7A9mutations inGreek cystinuria patients [J]. Mol Genet Metab, 2008,95(3): 192-193.

[28] WONG KA, MEIN R, WASS M, et al. The geneticdiversity of cystinuria in a UK population of patients [J].BJU Int, 2015, 116(1): 109-116.

[29] YUEN YP, LAM CW, LAI CK, et al. Heterogeneousmutations in theSLC3A1andSLC7A9genes in Chinesepatients with cystinuria [J]. Kidney Int, 2006, 69(1): 123-128.

[30] 1000 GENOMES PROJECT CONSORTIUM; AUTON A,BROOKS LD, et al. A global reference for human geneticvariation [J]. Nature, 2015, 526(7571): 68-74.

[31] MAHDAVI M, KOULIVAND L, KHORRAMI M, et al.In silico analysis ofSLC3A1andSLC7A9mutations in Iranianpatients with Cystinuria [J]. Mol Biol Rep, 2018, 45(5):1165-1173.

[32] MARTELL HJ, WONG KA, MARTIN JF, et al. Associatingmutations causing cystinuria with disease severity with theaim of providing precision medicine [J]. BMC Genomics,2017, 18 (5): 550.

[33] SERVAIS A, THOMAS K, DELLO STROLOGO L,et al. Cystinuria: clinical practice recommendation [J]. KidneyInt, 2021, 99(1): 48-58.

[34] TKACZYK M, GADOMSKA-PROKOP K, ZAŁUSKALEŚNIEWSKA I, et al. Clinical profile of a Polish cohortof children and young adults with cystinuria [J]. Ren Fail,2021, 43(1): 62-70.

[35]沈露明,陈雪花,徐彦,等.我国胱氨酸结石患者的临床和基因突变特点[C]//中国中西医结合学会泌尿外科专业委员会第十四次全国学术会议暨2016年广东省中西医结合学会泌尿外科专业委员会学术年会中国广东广州, 2016:1

[36] EDVARDSSON VO, GOLDFARB DS, LIESKE JC,et al. Hereditary causes of kidney stones and chronic kidneydisease [J]. Pediatr Nephrol, 2013, 28(10): 1923-1942.

[37] WOODARD LE, WELCH RC, VEACH RA, et al.Metabolic consequences of cystinuria [J]. BMC Nephrol, 2019,20(1): 227.

[38] REZAEE ME, RULE AD, PAIS VM JR. What are themain challenges to the pharmacological management ofcystinuria? [J]. Expert Opin Pharmacother, 2020, 21(2):131-133.

[39] NELSON CP, KURT Z M P, VENNA A, e t al.Pharmacological Dilutional Therapy Using the VasopressinAntagonist Tolvaptan for Young Patients With Cystinuria:A Pilot Investigation [J]. Urology, 2020, 144: 65-70.

[40] BAI Y, TANG Y, WANG J, et al. Tolvaptan treatmentof cystine urolithiasis in a mouse model of cystinuria [J].World J Urol, 2021, 39(1): 263-269.

[41] CIL O, PERWAD F. α-Lipoic Acid (ALA) ImprovesCystine Solubility in Cystinuria: Report of 2 Cases [J].Pediatrics, 2020, 145(5): e20192951.

[42] MOHAMMADI M, SHOHANI A, KHORAMI H, et al.The effect of selenium supplementation on cystine crystalvolume in patients with cystinuria [J]. Biomedicine (Taipei),2018, 8(4): 26.

[43] RIMER JD, AN Z, ZHU Z, et al. Crystal growth inhibitorsfor the prevention of L-cystine kidney stones through moleculardesign [J]. Science, 2010, 330(6002): 337-341.

[44] SUMOROK N, GOLDFARB DS. Update on cystinuria [J].Curr Opin Nephrol Hypertens, 2013, 22(4): 427-431.

[45] LEE MH, SAHOTA A, WARD MD, et al. Cystinegrowth inhibition through molecular mimicry: a new paradigmfor the prevention of crystal diseases [J]. Curr RheumatolRep, 2015, 17(5): 33.

[46] SAHOTA A, PARIHAR JS, CAPACCIONE KM, et al.Novel cystine ester mimics for the treatment of cystinuriainduced urolithiasis in a knockout mouse model [J]. Urology,2014, 84(5): 1249e9-e15.

[47] GOLDFARB DS. Potential pharmacologic treatments forcystinuria and for calcium stones associated with hyperuricosuria [J].Clin J Am Soc Nephrol, 2011,6(8): 2093-2097.

[48] ZEE T, BOSE N, ZEE J, et al. α-Lipoic acid treatmentprevents cystine urolithiasis in a mouse model of cystinuria [J].Nat Med, 2017, 23(3): 288-290.

[49] DAGA S, PALIT V, FORSTER JA, et al. An Updateon Evaluation and Management in Cystinuria [J]. Urology,2021, 149: 70-75.

[50] CREMER DR, RABELER R, ROBERTS A, et al.Long-term safety of alpha-lipoic acid (ALA) consumption:A 2-year study [J]. Regul Toxicol Pharmacol, 2006, 46(3):193-201.

[51] SINGH VK, RAI PK. Kidney stone analysis techniques andthe role of major and trace elements on their pathogenesis:a review [J]. Biophys Rev, 2014, 6(3/4): 291-310.

[52] LIU Y, XU H, ZHONG W, et al. Organic SeleniumAlleviated the Formation of Ethylene Glycol-Induced CalciumOxalate Renal Calculi by Improving Osteopontin Expressionand Antioxidant Capability in Dogs [J]. Biol Trace ElemRes, 2015, 168(2): 392-400.

[53] TORRES VE, CHAPMAN AB, DEVUYST O, et al.Tolvaptan in Later-Stage Autosomal Dominant PolycysticKidney Disease [J]. N Engl J Med, 2017, 377(20): 1930-1942.

[54] TORRES VE, CHAPMAN AB, DEVUYST O, et al.Tolvaptan in patients with autosomal dominant polycystic kidneydisease [J]. N Engl J Med, 2012, 367(25): 2407-2418.

[55] CHEBIB FT, PERRONE RD, CHAPMAN AB, et al.A Practical Guide for Treatment of Rapidly Progressive ADPKDwith Tolvaptan [J]. J Am Soc Nephrol, 2018, 29(10):2458-2470.

[56] ZHU M, WANG X, ZHOU Y, et al. Breast tumor-targeteddrug delivery via polymer nanocarriers: Endogenous andexogenous strategies [J]. J Appl Polym Sci, 2023,140(31):e54227.

田淑琳,刘薇,宋岩.胱氨酸尿症相关基因 SLC3A1 与 SLC7A9 突变与药物研究进展[J].泌尿外科杂志(电子版),2024,16(04):21-26.

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胱氨酸尿症（cystinuria，CSNU）是一种少见的遗传性疾病，全球流行率仅为1/7000，该疾病受种族和地理位置影响，流行性调查结果差异较大^[1-2]。胱氨酸结石症是CSNU最常见的临床表现，多数患者在20岁前发病^[3]。该类结石复发速度快，频率高，5年内复发率达80%，且损害肾功能，最终发展为慢性肾病，对人体造成不可逆的损害^[4-6]。胱氨酸结石分别占成人结石和儿童结石的1%~2%和6%~28%，中国胱氨酸结石患者构成比为0.57%，甚至更低^[4,7]。受多种因素局限，现有治疗方法无法根治该疾病。CSNU是一种常染色体遗传病，患者通常有家族遗传史。本文针对与CSNU相关的两种基因溶质载体家族3成员1（Solute Carrier Family 3 Member 1，SLC3A1）和溶质载体家族7成员9（Solute CarrierFamily 7 Member 9，SLC7A9）的遗传突变情况、基因型-表型相关性以及的近年来新药研究进展作一综述。

1 胱氨酸转运蛋白与相关编码基因 SLC3A1、SLC7A9

2 进展分型与临床分型对应关系

2.1 传统临床分型方法

2.2 基因分型方法

3 突变情况

3.1 基因分析

3.2 患者基因型-表型关联性

4 新型药物研究进展

4.1 L-胱氨酸二甲酯和 L-胱氨酸甲酯

4.2 ALA

4.3 硒

4.4 托伐普坦

5 小结与展望

CSNU受人群、种族的影响，基因突变率也有很大差异，应建立针对不同地区人群的基因数据库，了解不同人群间的差异。临床上不同基因型患者无法仅根据症状来区分，须行测序获取患者基因型，这可能与基因分组有关。在未来，可以开展新的分组方式探寻基因型-表型关联性以利于临床针对性治疗，尤其在基因治疗中通过CRISPR进行特定点位基因的改造和纠偏，也将是热点研究方向。部分有症状CSNU患者未检测到突变，可能存在外显子存在嵌入内含子的剪接位点突变被遗漏的现象，未来可以此为切入点进行基因测序。在多种药物精准递送方面，利用纳米技术等将分子靶点药物进行精准递送也是分子遗传病的前沿应用^[56]。

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