Genetics in kidney diseases

Son yıllarda genetik ve moleküler biyolojideki gelişmeler tıpta bir devrim niteliğindedir. Buna paralel olarak böbrek hastalıklarının moleküler temelleri ve dolayısıyla hastalık patogenezleri daha iyi anlaşılmaya başlanmıştır. Bu gelişmeler ileride nefrolojide yeni, daha kullanışlı tanısal belirteçlerin ve daha etkili tedavi hedeflerinin tanımlanmasına olanak sağlayacaktır. İlk kez onkolojide tüm genomu ilgilendiren ekspresyon analizleri yapılmış ve günümüzde birçok onkolojik malignensilerde moleküler yaklaşımlar tanı, sınıflandırma, ve tedavinin izleminde rutin olarak kullanılmaya başlanmıştır. Günümüzde moleküler tanı yaklaşımları nefrolojide de rutin olarak kullanılmaktadır. Ancak böbrek hastalığı olan hastaların moleküler karakterizasyonu ve böbreklerdeki hücresel heterojenite nedeniyle oldukça komplekstir. Böbrek biyopsi örneğinin de küçük boyutlu olması böbrek hastalıklarının doku düzeyinde analizine ilave bir güçlük katmaktadır. Bu nedenle böbrek hastalıklarıyla ilişkili biyolojik sıvılarda non-invazif analiz yöntemlerinin geliştirilmesine gereksinim vardır. Bu yazıda, böbrek hastalıklarının moleküler temelleriyle ilgili son gelişmeler üzerinde durulacaktır.

Böbrek hastalıklarında genetik

During the last two decades, developments in molecular biology and genetics have caused a revolution in medicine. Advances in gene cloning, gene mapping, and mutation analysis have contributed to an incredible amount of new information regarding the biological and pathophysiological basis for human diseases including kidney diseases. In monogenic diseases , a mutation of a single gene is sufficient to cause the disease. Conversely, in polygenic disorders, mutations of multiple genes are necessary to result in a disease. Progressive chronic kidney disease remains a major challenge in nephrology. Genome-wide expression analysis of disease processes has been pioneered in onco logy, and molecular approaches have now been included in the initial diagnosis. Although we still have difficulties in sample analyses of the kidneys, some of the molecular diagnostic approaches are now used routinely in nephrology as well. In this review, recent developments in the field of the molecular bases of kidney diseases will be addressed.

PDF

___

1. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science 2008; 322: 881-8. [CrossRef]
2. George AL Jr, Neilson EG. Genetics of kidney disease. Am J Kidney Dis 2000; 35: S160-9. [CrossRef]
3. Khoury MJ, Wagener DK. Epidemiological evaluationof the use of genetics to improve the predictive value ofdisease risk factors. Am J Hum Genet 1995; 56: 835-44.
4. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139-44. [CrossRef]
5. Hildebrandt F. Genetic kidney diseases. Lancet 2010; 375: 1287-95. [CrossRef]
6. Machuca E, Benoit G, Antignac C. Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum Mol Genet 2009; 18: R185-94. [CrossRef]
7. Kestila M, Mannikko M, Holmberg C, Tryggvason K, Peltonen L. Congenital nephrotic syndrome of the Finnish type is not associated with the Pax-2 gene despite the promising transgenic animal model. Genomics 1994; 19: 570-2. [CrossRef]
8. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000; 24: 349-54. [CrossRef]
9. Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A. Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2002; 13: 388-93.
10. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 2006; 38: 1397-405. [CrossRef]
11. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000; 24: 251-6. [CrossRef]
12. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005; 37: 739-44. [CrossRef]
13. Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, et al. Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2008; 19: 365-71. [CrossRef]
14. McCarthy HJ, Saleem MA. Genetics in clinical practice: nephrotic and proteinuric syndromes. Nephron Exp Nephrol 2011; 118: e1-8. [CrossRef]
15. Kashtan CE, Michael AF. Alport syndrome: from bedside to genome to bedside. Am J Kidney Dis 1993: 22: 627-40.
16. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport syndrome: natural history in 195 families and genotypephenotype correlations in males. J Am Soc Nephrol 2000: 11: 649-57.
17. Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Meta-analysis of genotypephenotype correlation in X-linked Alport syndrome:impact on clinical counseling. Nephrol DialTransplant 2002: 17: 1218-27. [CrossRef]
18. Gubler MC. Inherited diseases of the glomerular basement membrane. Nat Clin Pract Nephrol 2008; 4: 24-37. [CrossRef]
19. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 2009; 76: 149-68. [CrossRef]
20. Harris PC, Rossetti S. Molecular diagnostics of ADPKD coming of age. Clin J Am Soc Nephrol 2008; 3: 1-2. [CrossRef]
21. Otto EA, Trapp ML, Schultheiss UT, Helou J, Quarmby LM, Hildebrandt F. NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis. J Am Soc Nephrol 2008: 19: 587-92. [CrossRef]
22. Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007; 18: 1855-71. [CrossRef]
23. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, et al.Genetic heterogeneity of Bartters syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 1996; 14: 152-6. [CrossRef]
24. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartters syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996; 13: 183-8. [CrossRef]
25. Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, et al. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 2001; 29: 310-4. [CrossRef]
26. Estevez R, Boettger T, Stein V, Birkenhager R, Otto E, Hildebrandt F, et al. Barttin is a Cl channelbeta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature 2001; 414: 558-61. [CrossRef]
27. Knoers NV. Inherited forms of renal hypomagnesemia: an update. Pediatr Nephrol 2009; 24: 697-705. [CrossRef]
28. Konrad M, Schlingmann KP, Gudermann T. Insights into the molecular nature of magnesium homeostasis. Am J Physiol Renal Physiol 2004; 286: F599-605. [CrossRef]
29. Deen PM, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, van Os CH, et al. Requirement of human renal water channel aquaporin-2 for vasopressin- dependent concentration of urine. Science 1994; 264: 92-5. [CrossRef]
30. Sayer JA. The genetics of nephrolithiasis. Nephron Exp Nephrol 2008; 110: e37-43. [CrossRef]
31. Söylemezoğlu O, Ozkaya O, Gönen S, Misirlioğlu M, Kalman S, Buyan N. Vitamin D receptor gene polymorphism in hypercalciuric children. Pediatr Nephrol 2004; 19: 724-7. [CrossRef]
32. Ozkaya O, Söylemezoğlu O, Misirlioğlu M, Gönen S, Buyan N, Hasanoğlu E. Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 2003; 44: 150-4. [CrossRef]