Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?

İnci Hande Yener; Didem Dayangaç Erden

Derleme

Monogenic disorders and modifier genes: Is genotype predictive of phenotype?

Yıl 2014, Cilt: 27 Sayı: 2, 96 - 101, 20.05.2014

İnci Hande Yener Didem Dayangaç Erden

Öz

Although monogenic disorders are caused by mutations in one
gene, phenotypic variability occurs in patients with the same
genotype and disease expressivity changes. Modifier genes are
one of the main factors that affect disease severity. In monogenic
disorders such as spinal muscular atrophy (SMA), familial
Mediterranean fever (FMF) or cystic fibrosis (CF), more than one
gene that modifies the course of the disease has been detected.
High throughput techniques used in the genomics field will
provide functional research on modifier genes, pave the way to
establish genotype-to-phenotype correlations and explain the
pathophysiology of diseases.
The modifier genes which are associated with the most
common monogenic disorders in our population and their
functions are summarized in this review.

Anahtar Kelimeler

Monogenic disorders, Modifier genes, Genotype-tophenotype correlations

Kaynakça

1. Nussbaum RL, McInnes RR. Patterns of single-gene inheritance. In:Willard HF, Hamosh A, editors. Thompson& Thompson Genetics in Medicine. 7th ed. Philadelphia: WB Saunders, 2007 : 115-49.
2. Dipple KM, McCabe ERB. Modifier genes convert “Simple” Mendelian disorders to complex traits. Mol Genet Metab 2000; 7 : 43–50. doi:10.1006/mgme.2000.3052
3. Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, KehrerSawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132: 1077-130. doi: 10.1007/s00439-013-1331-2
4. Nadeau JH. Modifier genes and protective alleles in humans and mice. Curr Opin Genet Dev 2003; 13 : 290-5. doi: 10.1016/S0959- 437X(03)00061-3
5. Haldane J. The relative importance of principal and modifying genes in determining some human diseases. J Genet 1941; 41: 149–57. doi: 10.1007/BF02983018
6. Hamilton BA, Yu BD. Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 2012; 8: 1-7. doi: 10.1371/journal. pgen.1002644
7. Genin E, Feingold J, Clerget-Darpoux F. Identifying modifier genes of monogenic disease: strategies and difficulties. Hum Genet 2008; 124: 357–68. doi: 10.1007/s00439-008-0560-2
8. Nagel RL. Epistasis and the genetics of human diseases. C R Biol 2005; 328: 606-15. doi: 10.1016/j.crvi.2005.05.003
9. Na D, Rouf M, O’Kane CJ, Rubinsztein DC, Gsponer J. NeuroGeM, a knowledgebase of genetic modifiers in neurodegenerative diseases. MBC Med Genomics 2013; 6: 1-14. doi: 10.1186/1755-8794-6-52
10. Lehner B. Genotype to phenotype: lessons from model organisms for human genetics. Nat Rev Genet 2013; 14: 168-78. doi: 10.1038/ nrg3404
11. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of the spinal muscular atrophy determining gene. Cell 1995; 80: 155-65. doi:10.1016/0092-8674(95)90460-3
12. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15: 228-37. doi: 10.1002/(SICI)1098- 1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
13. Erdem H, Pehlivan S, Topaloğlu H, Özgüç M. Deletion analysis in Turkish patients with spinal muscular atrophy. Brain Dev 1999; 21: 86- 9. doi: 10.1016/S0387-7604(98)00063-1
14. Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8: 1177 - 83. doi: 10.1093/hmg/8.7.1177
15. Pearn J. Classification of spinal muscular atrophies. Lancet I 1980; 1: 919–22. doi: 10.1016/S0140-6736(80)90847-8
16. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16: 265 - 9. doi:10.1038/ng0797-265
17. Wirth B, Garbes L, Riessland M. How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches. Curr Opin Genet Dev 2013; 23: 330-8. doi: 10.1016/j.gde.2013.03.003
18. Oprea GE, Kröber S, McWhorter ML, et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008; 320 (5875): 524-7. doi: 10.1126/science.1155085
19. Bernal S, Also-Rallo E, Martínez-Hernández R, et al. Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings. Neuromuscul Disord 2011; 21: 413-9. doi: 10.1016/j. nmd.2011.03.009
20. Stratigopoulos G, Lanzano P, Deng L, et al. Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females. Arch Neurol 2010; 67 : 1252–6. doi: 10.1001/ archneurol.2010.239
21. Yanyan C, Yujin Q, Jinli B, Yuwei J, Hong W, Fang S. Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy. J Hum Genet 2014; 59: 24-7. doi: 10.1038/ jhg.2013.111
22. Yener İ H, Topaloğlu H, Erdem Özdamar S, Dayangaç Erden D. The investigation of the effect of modifier genes on spinal muscular atrophy phenotype. XIII. Ulusal Tıbbi Biyoloji ve Genetik Kongresi, 27-30 Ekim, 2013, Kuşadası. Kongre Kitapcığı, 2013:270. PS-06 11.
23. Ahmad S, Wang Y, Shaik GM, Burghes AH, Gangwani L. The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy. Hum Mol Genet 2012; 21: 2745–58. doi: 10.1093/hmg/dds102
24. Gangwani L, Flavell RA, Davis RJ. ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies. Mol Cell Biol 2005; 25 : 2744-56. doi: 10.1128/MCB.25.7.2744-2756.2005
25. Ackermann B, Kröber S, Torres-Benito L, et al. Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum Mol Genet 2013; 22: 1328-47. doi: 10.1093/hmg/dds540
26. Livhen A, Lengevitz P, Zewer D, et al. Criteria for the diagnosis of FMF. Arthritis Rheum 1997; 40: 1879-85. doi: 10.1002/ art.1780401023
27. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473–83. 28. Infevers veri tabanı, http://fmf.igh.cnrs.fr/infevers/. Erişim: 26.07.2013.
29. Peynircioğlu P, Yılmaz E. Ailevi Akdeniz ateşi hastalığının moleküler temeli. Hacettepe Tıp Derg 2006; 37 : 223-9.
30. Ben-Zvi I, Brandt B, Berkun Y, Lidar M, Livneh A. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF). Gene 2012; 491: 260-3. doi: 10.1016/j.gene.2011.10.005
31. Touitou I, Picot MC, Domingo C, et al. The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 2001; 44: 163-9. doi: 10.1002/1529-0131(200101)44:1<163:: AID-ANR20>3.0.CO;2-Z
32. Gershoni-Baruch R, Brik R, Zacks N, et al. The contribution of genotypes at the MEFV and SAA1 loci. Arthritis Rheum 2003; 48 : 1149-55. doi: 10.1002/art.10944
33. Medlej-Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 2004; 5: 1-6. doi:10.1186/1471-2350-5-4
34. Migita K, Agematsu K, Masumoto J, et al. The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. PLoS One. 2013; 8: 1-7. doi: 10.1371/journal. pone.0055227
35. Bakkaloglu A, Duzova A, Ozen S, et al. Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol 2004; 31: 1139-42.
36. Welsh MJ, Ramsey Bw, Accurso F. Cystic fibrosis. In: Scriver C, Vogelstein B, Beaudet AL, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGrawhill, 2001: 5121-88.
37. CFTR mutasyon veri tabanı http://www.genet.sickkids.on.ca . Erişim: 26.07.2013.
38. Kilinç MO, Ninis VN, Dağli E, et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet 2002; 113: 250–7. doi: 10.1002/ ajmg.10721
39. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995; 29: 777-807. doi: 10.1146/annurev. ge.29.120195.004021
40. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 2003; 67: 471-85. doi: 10.1046/j.1469-1809.2003.00028
41. Knowles MR. Gene modifiers of lung disease. Curr Opin Pulm Med 2006; 12: 416-21. doi: 10.1097/01.mcp.0000245707.59138.40
42. Weiler CA, Drumm ML. Genetic influences on cystic fibrosis lung disease severity. Front Pharmacol 2013; 4: 1-16. doi: 10.3389/ fphar.2013.00040
43. Accurso FJ, Sontag MK. Gene modifiers in cystic fibrosis. J Clin Invest 2008; 118: 839-41. doi: 10.1172/JCI35138
44. Collaco JM, Cutting GR. Update on gene modifiers in cystic fibrosis. Curr Opin Pul Med 2008; 14: 559-66. doi: 10.1097/ MCP.0b013e3283121cdc
45. Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med 2012; 2: 1-13. doi: 10.1101/cshperspect.a009548
46. Yarden J, Radojkovic D, De Boeck K, et al. Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype. J Med Genet 2004; 41: 629-33. doi: 10.1136/ jmg.2003.017947
47. Dorfman R, Sandford A, Taylor C, et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 2008; 118: 1040-9. doi: 10.1172/JCI33754.
48. Garred P, Pressler T, Lanng S, et al. Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease. Pediatr Pulmonol 2002; 33: 201–7. doi: 10.1002/ ppul.10064.
49. Brazova J, Sismova K, Vavrova V, et al. Polymorphisms of TGFbeta1 in cystic fibrosis patients. Clin Immunol 2006; 121: 350–7. doi: 10.1016/j.clim.2006.08.015
50. Arkwright PD, Laurie S, Super M, et al. TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax 2000; 55: 459–62. doi: 10.1136/thorax.55.6.459
51. Drumm ML, Konstan MW, Schluchter MD, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353: 1443-53. doi: 10.1056/NEJMoa051469
52. Gu Y, Harley IT, Henderson LB, et al. IFRD1 polymorphisms in cystic fibrosis with potential link to altered neutrophil function. Nature 2009; 458 (7241): 1039-42. doi: 10.1038/nature07811
53. Hillian AD, Londono D, Dunn JM, et al. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun 2008; 9 : 501-8. doi: 10.1038/gene.2008.42
54. Gisler FM, von Kanel T, Kraemer R, Schaller A, Gallati S. Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis. Eur J Hum Genet 2013; 21: 397-403. doi: 10.1038/ejhg.2012.181
55. Darrah R, McKone E, O’Connor C, et al. EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity. Physiol Genomics 2010; 41: 71-7. doi: 10.1152/physiolgenomics.00185.2009
56. Drumm ML, Ziady AG, Davis PB. Genetic variation and clinical heterogeneity in cystic fibrosis. Annu Rev Pathol. 2012; 7: 267-82. doi: 10.1146/annurev-pathol-011811-120900

Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?

Yıl 2014, Cilt: 27 Sayı: 2, 96 - 101, 20.05.2014

İnci Hande Yener Didem Dayangaç Erden

Öz

Tek gen hastalıkları, bir gendeki mutasyonlar sonucu ortaya
çıkmasına rağmen aynı genotipe sahip hastalar arasında fenotipik
çeşitlilik gözlenmekte ve hastalıkların penetrans ile ekspressivitesi
değişmektedir. Hastalık ciddiyetini değiştiren etkenler arasında ilk
sırada fenotipi modifiye edici genler gelmektedir. Klasik Mendel
türü kalıtım göstermesine rağmen fenotipik çeşitlilikler gözlenen
spinal müsküler atrofi (SMA), ailevi Akdeniz ateşi (AAA) ve
kistik fibrozis (KF) gibi tek gen hastalıklarında hastalık seyrini
etkileyen birden fazla gen saptanmıştır. Genombilim alanında
kullanılan yüksek çözünürlüklü teknikler sayesinde modifiye edici
genler hakkında fonksiyonel araştırmalar yapılabilecek, genotip ile
fenotip arasındaki ilişkinin kurulması ve hastalıkların
patofizyolojisini açıklamak mümkün olabilecektir.
Bu derlemede, toplumumuzda sık görülen tek gen
hastalıklarında tanımlanmış olan fenotipi modifiye edici genler ve
bu genlerin fonksiyonları özetlenmiştir.

Anahtar Kelimeler

Tek gen hastalıkları, Modifiye edici genler, Genotip-fenotip korelasyonu

Kaynakça

1. Nussbaum RL, McInnes RR. Patterns of single-gene inheritance. In:Willard HF, Hamosh A, editors. Thompson& Thompson Genetics in Medicine. 7th ed. Philadelphia: WB Saunders, 2007 : 115-49.
2. Dipple KM, McCabe ERB. Modifier genes convert “Simple” Mendelian disorders to complex traits. Mol Genet Metab 2000; 7 : 43–50. doi:10.1006/mgme.2000.3052
3. Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, KehrerSawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132: 1077-130. doi: 10.1007/s00439-013-1331-2
4. Nadeau JH. Modifier genes and protective alleles in humans and mice. Curr Opin Genet Dev 2003; 13 : 290-5. doi: 10.1016/S0959- 437X(03)00061-3
5. Haldane J. The relative importance of principal and modifying genes in determining some human diseases. J Genet 1941; 41: 149–57. doi: 10.1007/BF02983018
6. Hamilton BA, Yu BD. Modifier genes and the plasticity of genetic networks in mice. PLoS Genet 2012; 8: 1-7. doi: 10.1371/journal. pgen.1002644
7. Genin E, Feingold J, Clerget-Darpoux F. Identifying modifier genes of monogenic disease: strategies and difficulties. Hum Genet 2008; 124: 357–68. doi: 10.1007/s00439-008-0560-2
8. Nagel RL. Epistasis and the genetics of human diseases. C R Biol 2005; 328: 606-15. doi: 10.1016/j.crvi.2005.05.003
9. Na D, Rouf M, O’Kane CJ, Rubinsztein DC, Gsponer J. NeuroGeM, a knowledgebase of genetic modifiers in neurodegenerative diseases. MBC Med Genomics 2013; 6: 1-14. doi: 10.1186/1755-8794-6-52
10. Lehner B. Genotype to phenotype: lessons from model organisms for human genetics. Nat Rev Genet 2013; 14: 168-78. doi: 10.1038/ nrg3404
11. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of the spinal muscular atrophy determining gene. Cell 1995; 80: 155-65. doi:10.1016/0092-8674(95)90460-3
12. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15: 228-37. doi: 10.1002/(SICI)1098- 1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
13. Erdem H, Pehlivan S, Topaloğlu H, Özgüç M. Deletion analysis in Turkish patients with spinal muscular atrophy. Brain Dev 1999; 21: 86- 9. doi: 10.1016/S0387-7604(98)00063-1
14. Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8: 1177 - 83. doi: 10.1093/hmg/8.7.1177
15. Pearn J. Classification of spinal muscular atrophies. Lancet I 1980; 1: 919–22. doi: 10.1016/S0140-6736(80)90847-8
16. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16: 265 - 9. doi:10.1038/ng0797-265
17. Wirth B, Garbes L, Riessland M. How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches. Curr Opin Genet Dev 2013; 23: 330-8. doi: 10.1016/j.gde.2013.03.003
18. Oprea GE, Kröber S, McWhorter ML, et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008; 320 (5875): 524-7. doi: 10.1126/science.1155085
19. Bernal S, Also-Rallo E, Martínez-Hernández R, et al. Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings. Neuromuscul Disord 2011; 21: 413-9. doi: 10.1016/j. nmd.2011.03.009
20. Stratigopoulos G, Lanzano P, Deng L, et al. Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females. Arch Neurol 2010; 67 : 1252–6. doi: 10.1001/ archneurol.2010.239
21. Yanyan C, Yujin Q, Jinli B, Yuwei J, Hong W, Fang S. Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy. J Hum Genet 2014; 59: 24-7. doi: 10.1038/ jhg.2013.111
22. Yener İ H, Topaloğlu H, Erdem Özdamar S, Dayangaç Erden D. The investigation of the effect of modifier genes on spinal muscular atrophy phenotype. XIII. Ulusal Tıbbi Biyoloji ve Genetik Kongresi, 27-30 Ekim, 2013, Kuşadası. Kongre Kitapcığı, 2013:270. PS-06 11.
23. Ahmad S, Wang Y, Shaik GM, Burghes AH, Gangwani L. The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy. Hum Mol Genet 2012; 21: 2745–58. doi: 10.1093/hmg/dds102
24. Gangwani L, Flavell RA, Davis RJ. ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies. Mol Cell Biol 2005; 25 : 2744-56. doi: 10.1128/MCB.25.7.2744-2756.2005
25. Ackermann B, Kröber S, Torres-Benito L, et al. Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum Mol Genet 2013; 22: 1328-47. doi: 10.1093/hmg/dds540
26. Livhen A, Lengevitz P, Zewer D, et al. Criteria for the diagnosis of FMF. Arthritis Rheum 1997; 40: 1879-85. doi: 10.1002/ art.1780401023
27. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473–83. 28. Infevers veri tabanı, http://fmf.igh.cnrs.fr/infevers/. Erişim: 26.07.2013.
29. Peynircioğlu P, Yılmaz E. Ailevi Akdeniz ateşi hastalığının moleküler temeli. Hacettepe Tıp Derg 2006; 37 : 223-9.
30. Ben-Zvi I, Brandt B, Berkun Y, Lidar M, Livneh A. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF). Gene 2012; 491: 260-3. doi: 10.1016/j.gene.2011.10.005
31. Touitou I, Picot MC, Domingo C, et al. The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 2001; 44: 163-9. doi: 10.1002/1529-0131(200101)44:1<163:: AID-ANR20>3.0.CO;2-Z
32. Gershoni-Baruch R, Brik R, Zacks N, et al. The contribution of genotypes at the MEFV and SAA1 loci. Arthritis Rheum 2003; 48 : 1149-55. doi: 10.1002/art.10944
33. Medlej-Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 2004; 5: 1-6. doi:10.1186/1471-2350-5-4
34. Migita K, Agematsu K, Masumoto J, et al. The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. PLoS One. 2013; 8: 1-7. doi: 10.1371/journal. pone.0055227
35. Bakkaloglu A, Duzova A, Ozen S, et al. Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol 2004; 31: 1139-42.
36. Welsh MJ, Ramsey Bw, Accurso F. Cystic fibrosis. In: Scriver C, Vogelstein B, Beaudet AL, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGrawhill, 2001: 5121-88.
37. CFTR mutasyon veri tabanı http://www.genet.sickkids.on.ca . Erişim: 26.07.2013.
38. Kilinç MO, Ninis VN, Dağli E, et al. Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients. Am J Med Genet 2002; 113: 250–7. doi: 10.1002/ ajmg.10721
39. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995; 29: 777-807. doi: 10.1146/annurev. ge.29.120195.004021
40. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 2003; 67: 471-85. doi: 10.1046/j.1469-1809.2003.00028
41. Knowles MR. Gene modifiers of lung disease. Curr Opin Pulm Med 2006; 12: 416-21. doi: 10.1097/01.mcp.0000245707.59138.40
42. Weiler CA, Drumm ML. Genetic influences on cystic fibrosis lung disease severity. Front Pharmacol 2013; 4: 1-16. doi: 10.3389/ fphar.2013.00040
43. Accurso FJ, Sontag MK. Gene modifiers in cystic fibrosis. J Clin Invest 2008; 118: 839-41. doi: 10.1172/JCI35138
44. Collaco JM, Cutting GR. Update on gene modifiers in cystic fibrosis. Curr Opin Pul Med 2008; 14: 559-66. doi: 10.1097/ MCP.0b013e3283121cdc
45. Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med 2012; 2: 1-13. doi: 10.1101/cshperspect.a009548
46. Yarden J, Radojkovic D, De Boeck K, et al. Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype. J Med Genet 2004; 41: 629-33. doi: 10.1136/ jmg.2003.017947
47. Dorfman R, Sandford A, Taylor C, et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 2008; 118: 1040-9. doi: 10.1172/JCI33754.
48. Garred P, Pressler T, Lanng S, et al. Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease. Pediatr Pulmonol 2002; 33: 201–7. doi: 10.1002/ ppul.10064.
49. Brazova J, Sismova K, Vavrova V, et al. Polymorphisms of TGFbeta1 in cystic fibrosis patients. Clin Immunol 2006; 121: 350–7. doi: 10.1016/j.clim.2006.08.015
50. Arkwright PD, Laurie S, Super M, et al. TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax 2000; 55: 459–62. doi: 10.1136/thorax.55.6.459
51. Drumm ML, Konstan MW, Schluchter MD, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353: 1443-53. doi: 10.1056/NEJMoa051469
52. Gu Y, Harley IT, Henderson LB, et al. IFRD1 polymorphisms in cystic fibrosis with potential link to altered neutrophil function. Nature 2009; 458 (7241): 1039-42. doi: 10.1038/nature07811
53. Hillian AD, Londono D, Dunn JM, et al. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun 2008; 9 : 501-8. doi: 10.1038/gene.2008.42
54. Gisler FM, von Kanel T, Kraemer R, Schaller A, Gallati S. Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis. Eur J Hum Genet 2013; 21: 397-403. doi: 10.1038/ejhg.2012.181
55. Darrah R, McKone E, O’Connor C, et al. EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity. Physiol Genomics 2010; 41: 71-7. doi: 10.1152/physiolgenomics.00185.2009
56. Drumm ML, Ziady AG, Davis PB. Genetic variation and clinical heterogeneity in cystic fibrosis. Annu Rev Pathol. 2012; 7: 267-82. doi: 10.1146/annurev-pathol-011811-120900

Toplam 55 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	Türkçe
Konular	Klinik Tıp Bilimleri
Bölüm	Reviews
Yazarlar	İnci Hande Yener Bu kişi benim Didem Dayangaç Erden Bu kişi benim
Yayımlanma Tarihi	20 Mayıs 2014
Yayımlandığı Sayı	Yıl 2014 Cilt: 27 Sayı: 2

Kaynak Göster

APA	Yener, İ. H., & Dayangaç Erden, D. (2014). Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?. Marmara Medical Journal, 27(2), 96-101.
AMA	Yener İH, Dayangaç Erden D. Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?. Marmara Med J. Mayıs 2014;27(2):96-101.
Chicago	Yener, İnci Hande, ve Didem Dayangaç Erden. “Tek Gen hastalıkları Ve Modifiye Edici Genler: Genotip Her Zaman Fenotipi yansıtır mı?”. Marmara Medical Journal 27, sy. 2 (Mayıs 2014): 96-101.
EndNote	Yener İH, Dayangaç Erden D (01 Mayıs 2014) Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?. Marmara Medical Journal 27 2 96–101.
IEEE	İ. H. Yener ve D. Dayangaç Erden, “Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?”, Marmara Med J, c. 27, sy. 2, ss. 96–101, 2014.
ISNAD	Yener, İnci Hande - Dayangaç Erden, Didem. “Tek Gen hastalıkları Ve Modifiye Edici Genler: Genotip Her Zaman Fenotipi yansıtır mı?”. Marmara Medical Journal 27/2 (Mayıs 2014), 96-101.
JAMA	Yener İH, Dayangaç Erden D. Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?. Marmara Med J. 2014;27:96–101.
MLA	Yener, İnci Hande ve Didem Dayangaç Erden. “Tek Gen hastalıkları Ve Modifiye Edici Genler: Genotip Her Zaman Fenotipi yansıtır mı?”. Marmara Medical Journal, c. 27, sy. 2, 2014, ss. 96-101.
Vancouver	Yener İH, Dayangaç Erden D. Tek gen hastalıkları ve modifiye edici genler: Genotip her zaman fenotipi yansıtır mı?. Marmara Med J. 2014;27(2):96-101.

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