UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

遗传性肾炎(Alport综合征)的遗传学、发病机制及病理学

Author
Clifford E Kashtan, MD
Section Editors
Tej K Mattoo, MD, DCH, FRCP
Richard J Glassock, MD, MACP
Deputy Editor
Melanie S Kim, MD
Translators
栾江威, 主任医师

引言

遗传性肾炎(或Alport综合征)是一种进行性遗传性肾小球疾病，常伴有感音神经性聋和眼异常[1-4]。据估计此病的患病率约为每50,000次活产新生儿中有一例[5]。据报道，新增的终末期肾脏病(end-stage renal disease, ESRD)病例中有0.3%-2.3%为Alport综合征[6,7]。

Alport综合征的发病机制、遗传学及肾脏病理学将总结在此。Alport综合征的临床表现及病程、诊断和治疗将单独讨论。 (参见“遗传性肾炎(Alport综合征)的临床表现、诊断和治疗”)

发病机制

偶然观察到大多数Alport综合征患者的肾小球基底膜(glomerular basement membrane, GBM)不结合来自有抗-GBM抗体疾病(包括肺出血肾炎综合征)患者的抗体，帮助阐明了Alport综合征的发病机制[3,8-10]。这些发现提示Ⅳ型胶原的异常，而Ⅳ型胶原蛋白是抗-GBM抗体的目标蛋白。随后的研究证实了主要的异常存在于Ⅳ型胶原，接下来的章节将详细讨论。

遗传学 — Alport综合征主要为基底膜异常，而编码Ⅳ型胶原家族蛋白的数个编码基因发生突变引起这种异常。

Ⅳ型胶原分子由3股α链组成，呈三股螺旋结构，通过C-端非胶原结构域以特定方式交互在一起[9]。6条不同的Ⅳ型胶原链由6个不同的基因编码，这些基因以头对头的方式配对分布于3条染色体上。

             

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: 2017-06 . | This topic last updated: 2017-04-28.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Grünfeld JP. The clinical spectrum of hereditary nephritis. Kidney Int 1985; 27:83.
  2. Kashtan CE, Michael AF. Alport syndrome. Kidney Int 1996; 50:1445.
  3. Kashtan CE. Familial hematuria due to type IV collagen mutations: Alport syndrome and thin basement membrane nephropathy. Curr Opin Pediatr 2004; 16:177.
  4. Massella L, Onetti Muda A, Faraggiana T, et al. Epidermal basement membrane alpha 5(IV) expression in females with Alport syndrome and severity of renal disease. Kidney Int 2003; 64:1787.
  5. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000; 58:925.
  6. Persson U, Hertz JM, Wieslander J, Segelmark M. Alport syndrome in southern Sweden. Clin Nephrol 2005; 64:85.
  7. Heidet L, Gubler MC. The renal lesions of Alport syndrome. J Am Soc Nephrol 2009; 20:1210.
  8. McCoy RC, Johnson HK, Stone WJ, Wilson CB. Absence of nephritogenic GBM antigen(s) in some patients with hereditary nephritis. Kidney Int 1982; 21:642.
  9. Hudson BG. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J Am Soc Nephrol 2004; 15:2514.
  10. Hudson BG, Kalluri R, Gunwar S, et al. The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from anti-GBM nephritis after renal transplantation. Kidney Int 1992; 42:179.
  11. Fallerini C, Dosa L, Tita R, et al. Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet 2014; 86:252.
  12. Morinière V, Dahan K, Hilbert P, et al. Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol 2014; 25:2740.
  13. Heiskari N, Zhang X, Zhou J, et al. Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome. J Am Soc Nephrol 1996; 7:702.
  14. Tryggvason K, Zhou J, Hostikka SL, Shows TB. Molecular genetics of Alport syndrome. Kidney Int 1993; 43:38.
  15. Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 1998; 9:1736.
  16. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med 2003; 348:2543.
  17. Torra R, Tazón-Vega B, Ars E, Ballarín J. Collagen type IV (alpha3-alpha4) nephropathy: from isolated haematuria to renal failure. Nephrol Dial Transplant 2004; 19:2429.
  18. Barker DF, Hostikka SL, Zhou J, et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 1990; 248:1224.
  19. Antignac C, Knebelmann B, Drouot L, et al. Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression. J Clin Invest 1994; 93:1195.
  20. Rheault MN, Kren SM, Thielen BK, et al. Mouse model of X-linked Alport syndrome. J Am Soc Nephrol 2004; 15:1466.
  21. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol 2003; 14:2603.
  22. Rheault MN, Kren SM, Hartich LA, et al. X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome. Nephrol Dial Transplant 2010; 25:764.
  23. Mochizuki T, Lemmink HH, Mariyama M, et al. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 1994; 8:77.
  24. Longo I, Scala E, Mari F, et al. Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families. Nephrol Dial Transplant 2006; 21:665.
  25. Dagher H, Buzza M, Colville D, et al. A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome. Am J Kidney Dis 2001; 38:1217.
  26. van der Loop FT, Heidet L, Timmer ED, et al. Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int 2000; 58:1870.
  27. Longo I, Porcedda P, Mari F, et al. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 2002; 61:1947.
  28. Pescucci C, Mari F, Longo I, et al. Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 2004; 65:1598.
  29. Pochet JM, Bobrie G, Landais P, et al. Renal prognosis in Alport's and related syndromes: influence of the mode of inheritance. Nephrol Dial Transplant 1989; 4:1016.
  30. Gross O, Netzer KO, Lambrecht R, et al. Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrol Dial Transplant 2003; 18:1122.
  31. Kim Y, Kleppel MM, Butkowski R, et al. Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Pathol 1991; 138:413.
  32. Kobayashi T, Uchiyama M. Characterization of assembly of recombinant type IV collagen alpha3, alpha4, and alpha5 chains in transfected cell strains. Kidney Int 2003; 64:1986.
  33. Nakanishi K, Yoskikawa N, Iijima K, Nakamura H. Expression of type IV collagen alpha 3 and alpha 4 chain mRNA in X-linked Alport syndrome. J Am Soc Nephrol 1996; 7:938.
  34. Kalluri R, Shield CF, Todd P, et al. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 1997; 99:2470.
  35. Miner JH, Sanes JR. Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol 1996; 135:1403.
  36. Harvey SJ, Zheng K, Sado Y, et al. Role of distinct type IV collagen networks in glomerular development and function. Kidney Int 1998; 54:1857.
  37. Abrahamson DR, Isom K, Roach E, et al. Laminin compensation in collagen alpha3(IV) knockout (Alport) glomeruli contributes to permeability defects. J Am Soc Nephrol 2007; 18:2465.
  38. Kashtan CE. Animal models of Alport syndrome. Nephrol Dial Transplant 2002; 17:1359.
  39. Yoshioka K, Hino S, Takemura T, et al. Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. Am J Pathol 1994; 144:986.
  40. Zehnder AF, Adams JC, Santi PA, et al. Distribution of type IV collagen in the cochlea in Alport syndrome. Arch Otolaryngol Head Neck Surg 2005; 131:1007.
  41. Muda AO, Massella L, Giannakakis K, et al. Confocal microscopy of the skin in the diagnosis of X-linked Alport syndrome. J Invest Dermatol 2003; 121:208.
  42. Patey-Mariaud de Serre N, Garfa M, Bessiéres B, et al. Collagen alpha5 and alpha2(IV) chain coexpression: analysis of skin biopsies of Alport patients. Kidney Int 2007; 72:512.
  43. Su J, Liu ZH, Zeng CH, et al. Quantitative analysis of type IV collagen subchains in the glomerular basement membrane of patients with Alport syndrome with confocal microscopy. Nephrol Dial Transplant 2006; 21:1838.
  44. Naito I, Kawai S, Nomura S, et al. Relationship between COL4A5 gene mutation and distribution of type IV collagen in male X-linked Alport syndrome. Japanese Alport Network. Kidney Int 1996; 50:304.
  45. Cheong HI, Kashtan CE, Kim Y, et al. Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome. Lab Invest 1994; 70:553.
  46. Merchant SN, Burgess BJ, Adams JC, et al. Temporal bone histopathology in alport syndrome. Laryngoscope 2004; 114:1609.
  47. Dahan K, Heidet L, Zhou J, et al. Smooth muscle tumors associated with X-linked Alport syndrome: carrier detection in females. Kidney Int 1995; 48:1900.
  48. Rumpelt HJ. Hereditary nephropathy (Alport syndrome): correlation of clinical data with glomerular basement membrane alterations. Clin Nephrol 1980; 13:203.