遗传性肾病研究的现状及未来
作者：梅长林 陈楠
单位：梅长林(200003上海，第二军医大学长征医院肾内科)；陈楠(上海第二医科大学瑞金医院肾内科)
关键词：
中华肾病杂志000401遗传性肾病(inheritedkidneydiseases)是由基因突变所致，并按孟德尔定律遗传子代的一组肾脏疾病，包括遗传性肾囊肿疾病，如常染色体显性遗传型多囊肾病(autosomaldominantpolycystickidneydisease，ADPKD)；遗传性肾小球疾病，如遗传性肾炎(Alportsyndrome，AS)、薄基底膜肾病(thinbasementmembranedisease，TBMD)和Fabry病；遗传性肾小管疾病，如家族性抗维生素D佝偻病(familialvitamineDresistantrickets，VDRR)；以及遗传代谢性肾病，如胱氨酸肾病等。过去，对遗传性肾病认识不足，发现率低。随着现代分子生物学技术的进步，遗传性肾病的基因突变检测，发病机制研究及诊断技术水平有了很大提高，基因治疗也给遗传性肾病患者带来了治愈的希望。ADPKD是一种最常见的单基因遗传性肾病，人群发病率约1/1000t[1]。家系中代代有人患病，子代患病机率为50%，男女患病相等，患者等位基因为杂合子是其遗传特点。目前ADPKD研究主要有以下进展：(1)分子遗传学研究：研究表明引起ADPKD的突变基因至少有3种，按发现先后，分别称为PKD1、PKD2和PKD3。PKD3尚未在染色体上定位，PKD1和PKD2引起ADPKD分别占85%和15%，均已在染色体上定位和克隆。PKD1位于第16人染色体短臂1区3带上(16p13)，蛋白质产物是由4302个氨基酸残基构成的一种糖蛋白，称为多囊蛋白-1，位于细胞膜上[2]。本刊今期发表的文章表明多囊蛋白-1在正常肾小球囊和肾小管上皮细胞均有表达，在胎肾肾小管和多囊肾衬里上皮表达显著增强。PKD2位于第4人染色体长臂2区1带至3带之间(4q21～23)，翻译产物称为多囊蛋白-2。由968个氨基酸残基构成，同样是一种膜蛋白。多囊蛋白功能未明，推测它们主要介导细胞-细胞，细胞-基质A之间的相互作用，促进上皮细胞分化，维持膜蛋白正(全文见PDF)
, http://www.100md.com
参考文献：
[1]Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med,1993,329:332-342.
[2]Murcia NS,Woychik RP,Avner ED.The molecular biology of polycystic kidney disease.Pediatr Nephrol,1998,12:721-726.
[3]Brasier JL,Henske EP.Loss of the polycystic kidney disease(PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis.J Clin Invest,1997,99:194-199.
, 百拇医药
[4]Grantham JJ.The etiology,pathogenesis,and treatment of autosomal dominant polycystic kidney disease:recent advances.Am J Kidney Dis 1996,28:788-803.
[5]Li HP,Geng L,Burrow CR,et al.Identification of phosphorylation site in the PKD1-encoded protein c-terminal domain.Biochem Biophys Res Commun,1999,259:356-363.
[6]Kashtan CE,Michael AF,Sibley RK,et al.Hereditary nephritis:Alport syndrome and thin glomerular basement membrane disease.In:Tisher CC,Brenner BM,eds.Renal pathology.2nd ed.Philadelphia:Lippincott,1994,1239-1266.
, 百拇医药
[7]Kashtan CE.Alport syndrome and thin glomerular basement membrane disease.J Am Soc Nephrol,1998,9:1736-1750.
[8]Tryggvason K,Heikkila P,Pettersson E,et al.Can Alport syndrome be treated by gene therapy?Kidney Iht,1997,51:1493-1499.
[9]Lanteri M,Wilson D,Savige J,et al.Clinical features in two patients with IgA glomerulonephritis and thin-basement-membrane disease.Nephrol Dial Transplant,1996,11:791-793.
, 百拇医药
[10]Topaloglu AK,Ashley GA,Tong B,et al.Twenty novel mutation in the alpha-galactosidase A gene causing Fabry disease.Mol Med,1999,5:806-811.
[11]Schiffmann R,Murray GJ,Treco D,et al.Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.Proc Natl Acad Sci USA,2000,97:365-370.
[12]Takenaka T,Qin G,Brady RO,et al.Circulating alpha-galactosidase A derived from transduced bone marrow cells:relevance for corrective gene transfer for Fabry disease.Hum Gene Ther,1999,10:1931-1939.
, http://www.100md.com
[13]Abe A,Arend LJ,Lee L,et al.Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase.Kidney Int,2000,57:446-454.
[14]Dreyer SD,Zhou G,Baldini A,et al.Mutation in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail-patella syndrome.Nat Genet,1998,19:47-50.
[15]Clough MV,Hamlington JD,Mclntosh I,et al.Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients.Hum Mutat,1999,14:459-465.
[16]Feingold M,Itzchak Y,Goodman RM.Ultrasound prenatal diagnosis in the nail patella syndrome.Prenat Diagn,1998,18:854-856.
收稿日期：2000-07-06, http://www.100md.com
单位：梅长林(200003上海，第二军医大学长征医院肾内科)；陈楠(上海第二医科大学瑞金医院肾内科)
关键词：
中华肾病杂志000401遗传性肾病(inheritedkidneydiseases)是由基因突变所致，并按孟德尔定律遗传子代的一组肾脏疾病，包括遗传性肾囊肿疾病，如常染色体显性遗传型多囊肾病(autosomaldominantpolycystickidneydisease，ADPKD)；遗传性肾小球疾病，如遗传性肾炎(Alportsyndrome，AS)、薄基底膜肾病(thinbasementmembranedisease，TBMD)和Fabry病；遗传性肾小管疾病，如家族性抗维生素D佝偻病(familialvitamineDresistantrickets，VDRR)；以及遗传代谢性肾病，如胱氨酸肾病等。过去，对遗传性肾病认识不足，发现率低。随着现代分子生物学技术的进步，遗传性肾病的基因突变检测，发病机制研究及诊断技术水平有了很大提高，基因治疗也给遗传性肾病患者带来了治愈的希望。ADPKD是一种最常见的单基因遗传性肾病，人群发病率约1/1000t[1]。家系中代代有人患病，子代患病机率为50%，男女患病相等，患者等位基因为杂合子是其遗传特点。目前ADPKD研究主要有以下进展：(1)分子遗传学研究：研究表明引起ADPKD的突变基因至少有3种，按发现先后，分别称为PKD1、PKD2和PKD3。PKD3尚未在染色体上定位，PKD1和PKD2引起ADPKD分别占85%和15%，均已在染色体上定位和克隆。PKD1位于第16人染色体短臂1区3带上(16p13)，蛋白质产物是由4302个氨基酸残基构成的一种糖蛋白，称为多囊蛋白-1，位于细胞膜上[2]。本刊今期发表的文章表明多囊蛋白-1在正常肾小球囊和肾小管上皮细胞均有表达，在胎肾肾小管和多囊肾衬里上皮表达显著增强。PKD2位于第4人染色体长臂2区1带至3带之间(4q21～23)，翻译产物称为多囊蛋白-2。由968个氨基酸残基构成，同样是一种膜蛋白。多囊蛋白功能未明，推测它们主要介导细胞-细胞，细胞-基质A之间的相互作用，促进上皮细胞分化，维持膜蛋白正(全文见PDF)
, http://www.100md.com
参考文献：
[1]Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med,1993,329:332-342.
[2]Murcia NS,Woychik RP,Avner ED.The molecular biology of polycystic kidney disease.Pediatr Nephrol,1998,12:721-726.
[3]Brasier JL,Henske EP.Loss of the polycystic kidney disease(PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis.J Clin Invest,1997,99:194-199.
, 百拇医药
[4]Grantham JJ.The etiology,pathogenesis,and treatment of autosomal dominant polycystic kidney disease:recent advances.Am J Kidney Dis 1996,28:788-803.
[5]Li HP,Geng L,Burrow CR,et al.Identification of phosphorylation site in the PKD1-encoded protein c-terminal domain.Biochem Biophys Res Commun,1999,259:356-363.
[6]Kashtan CE,Michael AF,Sibley RK,et al.Hereditary nephritis:Alport syndrome and thin glomerular basement membrane disease.In:Tisher CC,Brenner BM,eds.Renal pathology.2nd ed.Philadelphia:Lippincott,1994,1239-1266.
, 百拇医药
[7]Kashtan CE.Alport syndrome and thin glomerular basement membrane disease.J Am Soc Nephrol,1998,9:1736-1750.
[8]Tryggvason K,Heikkila P,Pettersson E,et al.Can Alport syndrome be treated by gene therapy?Kidney Iht,1997,51:1493-1499.
[9]Lanteri M,Wilson D,Savige J,et al.Clinical features in two patients with IgA glomerulonephritis and thin-basement-membrane disease.Nephrol Dial Transplant,1996,11:791-793.
, 百拇医药
[10]Topaloglu AK,Ashley GA,Tong B,et al.Twenty novel mutation in the alpha-galactosidase A gene causing Fabry disease.Mol Med,1999,5:806-811.
[11]Schiffmann R,Murray GJ,Treco D,et al.Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.Proc Natl Acad Sci USA,2000,97:365-370.
[12]Takenaka T,Qin G,Brady RO,et al.Circulating alpha-galactosidase A derived from transduced bone marrow cells:relevance for corrective gene transfer for Fabry disease.Hum Gene Ther,1999,10:1931-1939.
, http://www.100md.com
[13]Abe A,Arend LJ,Lee L,et al.Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase.Kidney Int,2000,57:446-454.
[14]Dreyer SD,Zhou G,Baldini A,et al.Mutation in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail-patella syndrome.Nat Genet,1998,19:47-50.
[15]Clough MV,Hamlington JD,Mclntosh I,et al.Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients.Hum Mutat,1999,14:459-465.
[16]Feingold M,Itzchak Y,Goodman RM.Ultrasound prenatal diagnosis in the nail patella syndrome.Prenat Diagn,1998,18:854-856.
收稿日期：2000-07-06, http://www.100md.com