原发开角型青光眼家系一新的TIGR基因突变
摘要
背景
青光眼是现今主要的致盲疾病之一。估计全球约有6,700,000人因患青光眼而双目失明。世界范围内,原发性开角型青光眼(POAG)是最常见的亚型,在长期的医学实践中,人们发现很多青光眼有明显的遗传倾向。最近一些研究显示某些基因的缺陷是导致青光眼的原因。在众多的研究结果中,最有意义的是将POAG致病的相关基因定位于染色体1q21至1q31之间。位于该区域的小梁网糖皮质激素诱导反应蛋白(trabecular meshwork induced glucocorticoid response protein,TIGR)基因(OMIM:~*601652)也被证实与POAG患者的发病有关,并发现多个突变点。但是目前致病性TIGR基因突变的报道大多数源自白人和黑人,全球范围内有关中国人TIGR致病性基因突变的报导很少。
目的:
探讨一中国人原发开角型青光眼家系的TIGR基因缺陷及其突变。
方法:
(1) POAG家系的临床及遗传学的研究
对1996-2004年临床中所接触到的POAG患者及其家属进行家族遗传资料的询问及全面的眼科检查。临床检查内容主要包括:视力和屈光检查、裂隙灯检查、直接或间接眼底镜检查、视野检查(Octopus型全自动视野分析仪,美国)、眼压、房角镜检查以及视网膜断层仪(Retina Tomograph Ⅱ,Heidelberg Engineering,德国)摄影等。根据临床检查结果将家系成员分为青光眼患者、青光眼可疑者和正常者三类。POAG患者的诊断标准为:(1)特征性青光眼
Background:Primary open angle glaucoma (POAG) is one of the leading causes of blindness worldwide. Defects in trabecular -meshwork inducible glucocorticoid response. (TIGR) gene (OMIM: ~*601652) have been shown to be associated with POAG. Many mutations in TIGR gene have been reported. However, in the literature, descriptions of disease-causing TIGR mutations in Chinese population are few.Purpose:To determine the possible TIGR molecular genetic defect underlying POAG in China and to identify the pathogenic mutation causing the disease.Methods:(1) Clinical and genetic study of the POAG familyA large POAG family was chosen from many POAG families we investigated during the last 8 years to be complete studied in this
program. The majority of 1 branch of this large Chinese POAG family was personally examined by two senior ophthalmologists. The diagnoses were made by both doctors according to the signs of elevated intraocular pressure (IOP), glaucomatous optic neuropathy and glaucomatous visual field defect. (2) Molecular genetic study of the POAG family1. Isolation of the genomic DNA: genomic DNA was extracted from the family members' blood by using DNA Isolation Kits for Mammalian Blood(Roche Biochimical, Inc).2. PCR primer design: PCR primers were designed to amplify all coding sequences of the TIGR gene plus the flanking sites.3. PCR amplification: PCR amplification was performed in a 50ul or 20ul volume4. Purification of the PCR products: PCR products were purified using Gel purification Kits(Omega, USA)5. Mutation screening: 100 normal control subjects were screened by single strand conformational polymorphism analysis for the mutation.Results:(1) Genetic analysis of the POAG family
This 5 generation family was composed of 62 members, including 46 males and 16 females. There were 7POAG patients, 3 glaucoma suspects and 10 normal subjects among the family members who donated their blood samples. All POAG patients had elevated intraocular pressures that could not be adequately lowered by medications. Filtering surgery was performed on 6 of 7 affected family members. The remaining one has reached the late stage of POAG.(2) Molecular genetic analysis of the POAG familyA novel disease-causing missence mutation T455K in the third exon of the TIGR gene was identified in all affected family members, all glaucoma suspects and 4 individuals who have not shown apparently signs of glaucoma. None of the subjects without the mutation had glaucoma. Affected individuals with the T455K mutation showed variable onset between 26-59 years of age. The T455K mutation in TIGR gene was not found in the normal controls. A previously reported polymorphism 730+35 (A>G) in the second intron of the TIGR gene was detected in 4 individuals.Conclusion:The novel TIGR sequence alteration T455K that was highly
青光眼是现今主要的致盲疾病之一。估计全球约有6,700,000人因患青光眼而双目失明。世界范围内,原发性开角型青光眼(POAG)是最常见的亚型,在长期的医学实践中,人们发现很多青光眼有明显的遗传倾向。最近一些研究显示某些基因的缺陷是导致青光眼的原因。在众多的研究结果中,最有意义的是将POAG致病的相关基因定位于染色体1q21至1q31之间。位于该区域的小梁网糖皮质激素诱导反应蛋白(trabecular meshwork induced glucocorticoid response protein,TIGR)基因(OMIM:~*601652)也被证实与POAG患者的发病有关,并发现多个突变点。但是目前致病性TIGR基因突变的报道大多数源自白人和黑人,全球范围内有关中国人TIGR致病性基因突变的报导很少。
目的:
探讨一中国人原发开角型青光眼家系的TIGR基因缺陷及其突变。
方法:
(1) POAG家系的临床及遗传学的研究
对1996-2004年临床中所接触到的POAG患者及其家属进行家族遗传资料的询问及全面的眼科检查。临床检查内容主要包括:视力和屈光检查、裂隙灯检查、直接或间接眼底镜检查、视野检查(Octopus型全自动视野分析仪,美国)、眼压、房角镜检查以及视网膜断层仪(Retina Tomograph Ⅱ,Heidelberg Engineering,德国)摄影等。根据临床检查结果将家系成员分为青光眼患者、青光眼可疑者和正常者三类。POAG患者的诊断标准为:(1)特征性青光眼
Background:Primary open angle glaucoma (POAG) is one of the leading causes of blindness worldwide. Defects in trabecular -meshwork inducible glucocorticoid response. (TIGR) gene (OMIM: ~*601652) have been shown to be associated with POAG. Many mutations in TIGR gene have been reported. However, in the literature, descriptions of disease-causing TIGR mutations in Chinese population are few.Purpose:To determine the possible TIGR molecular genetic defect underlying POAG in China and to identify the pathogenic mutation causing the disease.Methods:(1) Clinical and genetic study of the POAG familyA large POAG family was chosen from many POAG families we investigated during the last 8 years to be complete studied in this
program. The majority of 1 branch of this large Chinese POAG family was personally examined by two senior ophthalmologists. The diagnoses were made by both doctors according to the signs of elevated intraocular pressure (IOP), glaucomatous optic neuropathy and glaucomatous visual field defect. (2) Molecular genetic study of the POAG family1. Isolation of the genomic DNA: genomic DNA was extracted from the family members' blood by using DNA Isolation Kits for Mammalian Blood(Roche Biochimical, Inc).2. PCR primer design: PCR primers were designed to amplify all coding sequences of the TIGR gene plus the flanking sites.3. PCR amplification: PCR amplification was performed in a 50ul or 20ul volume4. Purification of the PCR products: PCR products were purified using Gel purification Kits(Omega, USA)5. Mutation screening: 100 normal control subjects were screened by single strand conformational polymorphism analysis for the mutation.Results:(1) Genetic analysis of the POAG family
This 5 generation family was composed of 62 members, including 46 males and 16 females. There were 7POAG patients, 3 glaucoma suspects and 10 normal subjects among the family members who donated their blood samples. All POAG patients had elevated intraocular pressures that could not be adequately lowered by medications. Filtering surgery was performed on 6 of 7 affected family members. The remaining one has reached the late stage of POAG.(2) Molecular genetic analysis of the POAG familyA novel disease-causing missence mutation T455K in the third exon of the TIGR gene was identified in all affected family members, all glaucoma suspects and 4 individuals who have not shown apparently signs of glaucoma. None of the subjects without the mutation had glaucoma. Affected individuals with the T455K mutation showed variable onset between 26-59 years of age. The T455K mutation in TIGR gene was not found in the normal controls. A previously reported polymorphism 730+35 (A>G) in the second intron of the TIGR gene was detected in 4 individuals.Conclusion:The novel TIGR sequence alteration T455K that was highly
引文
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2. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbee DE, de Jong PT. The prevalence of primary open-angle glaucoma in a population-based study in The Netherlands. The Rotterdam Study. Ophthalmology. 1994 Nov;101(11):1851-5.
3. Tuck MW, Crick RP. The age distribution of primary open angle glaucoma. Ophthalmic Epidemiol. 1998 Dec;5(4): 173-83. Erratum in: Ophthalmic Epidemiol 1999 Mar;6(1):84.
4. Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1640-5.
5. McLEAN JA. Streptomycin resistance in the tubercule bacillus.Edinburgh Med J. 1950 Nov;57(11):547-56
6. FRANCOIS J. Ophthalmology and general medicine. Belg Tijdschr Geneesk. 1954 Dec 15;10(24):1145-65.
7. Polansky JR. HTM cell culture model for steroid effects on IOP: overview. In: Lutjen-Drecoll E, editor. Basic aspects of glaucoma research III: international symposium held at the Department of Anatomy, University of Erlangen; 1991 Sep 23-25; Nurnberg, Germany. Stuttgart, Germany: Schattauer; 1993. p. 307-18.
8. Polansky JR, Fauss DJ, Chen P, Chen H, Lutjen-Drecoll E, Johnson D, Kurtz RM, Ma ZD, Bloom E, Nguyen TD. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica 1997; 211:126-39.
9. Armaly MF. Inheritance of dexamethasone hypertension and glaucoma. Arch Ophthalmol. 1967 Jun;77(6):747-51.
10. Suden SLF, Alward W, Nichols BE, et al. Fine mapping of autosimal dominet juvenile open angle glaucoma region and evaluation of candidate genes. Genet. Res 1996; 6: 862-869
11. ARMALY MF. EFFECT OF CORTICOSTEROIDS ON INTRAOCULAR PRESSURE AND FLUID DYNAMICS. III. CHANGES IN VISUAL FUNCTION AND PUPIL SIZE DURING TOPICAL DEXAMETHASONE APPLICATION. Arch Ophthalmol. 1964 May;7I:636-44.
12. Sheffield VC, Stone EM, Alward WL, Drack AV, Johnson AT, Streb LM, Nichols BE. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet 1993; 4:47-50.
13. Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, Sunden SL, Nishimura D, Clark AF, Nystuen A, Nichols BE, Mackey DA, Ritch R, Kalenak JW, Craven ER, Sheffield VC. Identification of a gene that causes primary open angle glaucoma. Science 1997; 275:668-70. .
14. Fingert JH, Heon E, Liebmann JM, Yamamoto T, Craig JE, Rait J, Kawase K, Hoh ST, Buys YM, Dickinson J, Hockey RR, Williams-Lyn D, Trope G, Kitazawa Y, Ritch R, Mackey DA, Alward WL, Sheffield VC, Stone EM. Analysis of myocilin
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16. Suzuki Y, Shirato S, Taniguchi F, Ohara K, Nishimaki K, Ohta S. Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. Am J Hum Genet 1997; 61:1202-4.
17. Stoilova D, Child A, Brice G, Desai T, Barsoum-Homsy M, Ozdemir N, Chevrette L, Adam MF, Garchon HJ, Pitts Crick R, Sarfarazi M. Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma. J Med Genet 1998; 35:989-92.
18. Stoilova D, Child A, Brice G, Crick RP, Fleck BW, Sarfarazi M. Identification of a new 'TIGR' mutation in a family with juvenile-onset primary open angle glaucoma. Ophthalmic Genet 1997; 18:109-18.
19. Alward WL, Fingert JH, Coote MA, Johnson AT, Lerner SF, Junqua D, Durcan FJ, McCartney PJ, Mackey DA, Sheffield VC, Stone EM. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLCIA). N Engl J Med 1998; 338:1022-7.
20. Angius A, Pisano M, Sanca A, Casu G, Persico I, Pitzalis S, De Gioia E, Grignolo FM, Loi A, Sole G, Cao A, Spinelli P, Ghillotti G, Bonomi L, Fossarello M, Serra A, Gandolfi S, Alberti G, Maraini G, Serru A, Orzalesi N, Pirastu M. Molecular basis of open-angle glaucoma in Italy. Acta Ophthalmol Scand Suppl 1998; (227):16-7.
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22. Mansergh FC, Kenna PF, Ayuso C, Kiang AS, Humphries P, Farrar GJ. Novel mutations in the TIGR gene in early and late onset open angle glaucoma. Hum Mutat 1998; 11:244-51.
23. Mabuchi F, Yamagata Z, Kashiwagi K, Tang S, Iijima H, Tsukahara S. Analysis of myocilin gene mutations in Japanese patients with normal tension glaucoma and primary open-angle glaucoma. Clin Genet 2001; 59:263-8.
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47.Francois J, Heintz-de Bree CH, Tripathi RC. The cortisone test and the heredity of primary open-angle glaucoma. Am J Ophthalmol. 1966 Nov;62(5):844-52.
2. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbee DE, de Jong PT. The prevalence of primary open-angle glaucoma in a population-based study in The Netherlands. The Rotterdam Study. Ophthalmology. 1994 Nov;101(11):1851-5.
3. Tuck MW, Crick RP. The age distribution of primary open angle glaucoma. Ophthalmic Epidemiol. 1998 Dec;5(4): 173-83. Erratum in: Ophthalmic Epidemiol 1999 Mar;6(1):84.
4. Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1640-5.
5. McLEAN JA. Streptomycin resistance in the tubercule bacillus.Edinburgh Med J. 1950 Nov;57(11):547-56
6. FRANCOIS J. Ophthalmology and general medicine. Belg Tijdschr Geneesk. 1954 Dec 15;10(24):1145-65.
7. Polansky JR. HTM cell culture model for steroid effects on IOP: overview. In: Lutjen-Drecoll E, editor. Basic aspects of glaucoma research III: international symposium held at the Department of Anatomy, University of Erlangen; 1991 Sep 23-25; Nurnberg, Germany. Stuttgart, Germany: Schattauer; 1993. p. 307-18.
8. Polansky JR, Fauss DJ, Chen P, Chen H, Lutjen-Drecoll E, Johnson D, Kurtz RM, Ma ZD, Bloom E, Nguyen TD. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica 1997; 211:126-39.
9. Armaly MF. Inheritance of dexamethasone hypertension and glaucoma. Arch Ophthalmol. 1967 Jun;77(6):747-51.
10. Suden SLF, Alward W, Nichols BE, et al. Fine mapping of autosimal dominet juvenile open angle glaucoma region and evaluation of candidate genes. Genet. Res 1996; 6: 862-869
11. ARMALY MF. EFFECT OF CORTICOSTEROIDS ON INTRAOCULAR PRESSURE AND FLUID DYNAMICS. III. CHANGES IN VISUAL FUNCTION AND PUPIL SIZE DURING TOPICAL DEXAMETHASONE APPLICATION. Arch Ophthalmol. 1964 May;7I:636-44.
12. Sheffield VC, Stone EM, Alward WL, Drack AV, Johnson AT, Streb LM, Nichols BE. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet 1993; 4:47-50.
13. Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, Sunden SL, Nishimura D, Clark AF, Nystuen A, Nichols BE, Mackey DA, Ritch R, Kalenak JW, Craven ER, Sheffield VC. Identification of a gene that causes primary open angle glaucoma. Science 1997; 275:668-70. .
14. Fingert JH, Heon E, Liebmann JM, Yamamoto T, Craig JE, Rait J, Kawase K, Hoh ST, Buys YM, Dickinson J, Hockey RR, Williams-Lyn D, Trope G, Kitazawa Y, Ritch R, Mackey DA, Alward WL, Sheffield VC, Stone EM. Analysis of myocilin
mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999; 8:899-905.
15. Adam MF, Belmouden A, Binisti P, Brezin AP, Valtot F, Bechetoille A, Dascotte JC, Copin B, Gomez L, Chaventre A, Bach JF, Garchon HJ. Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Hum Mol Genet 1997; 6:2091-7.
16. Suzuki Y, Shirato S, Taniguchi F, Ohara K, Nishimaki K, Ohta S. Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan. Am J Hum Genet 1997; 61:1202-4.
17. Stoilova D, Child A, Brice G, Desai T, Barsoum-Homsy M, Ozdemir N, Chevrette L, Adam MF, Garchon HJ, Pitts Crick R, Sarfarazi M. Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma. J Med Genet 1998; 35:989-92.
18. Stoilova D, Child A, Brice G, Crick RP, Fleck BW, Sarfarazi M. Identification of a new 'TIGR' mutation in a family with juvenile-onset primary open angle glaucoma. Ophthalmic Genet 1997; 18:109-18.
19. Alward WL, Fingert JH, Coote MA, Johnson AT, Lerner SF, Junqua D, Durcan FJ, McCartney PJ, Mackey DA, Sheffield VC, Stone EM. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLCIA). N Engl J Med 1998; 338:1022-7.
20. Angius A, Pisano M, Sanca A, Casu G, Persico I, Pitzalis S, De Gioia E, Grignolo FM, Loi A, Sole G, Cao A, Spinelli P, Ghillotti G, Bonomi L, Fossarello M, Serra A, Gandolfi S, Alberti G, Maraini G, Serru A, Orzalesi N, Pirastu M. Molecular basis of open-angle glaucoma in Italy. Acta Ophthalmol Scand Suppl 1998; (227):16-7.
21. Brezin AP, Adam MF, Belmouden A, Lureau MA, Chaventre A, Copin B, Gomez L, De Dinechin SD, Berkani M, Valtot F, Rouland JF, Dascotte JC, Bach JF, Garchon HJ. Founder effect in GLCl A-linked familial open-angle glaucoma in Northern France. Am J Med Genet 1998; 76:438-45.
22. Mansergh FC, Kenna PF, Ayuso C, Kiang AS, Humphries P, Farrar GJ. Novel mutations in the TIGR gene in early and late onset open angle glaucoma. Hum Mutat 1998; 11:244-51.
23. Mabuchi F, Yamagata Z, Kashiwagi K, Tang S, Iijima H, Tsukahara S. Analysis of myocilin gene mutations in Japanese patients with normal tension glaucoma and primary open-angle glaucoma. Clin Genet 2001; 59:263-8.
24. Richards JE, Ritch R, Lichter PR, Rozsa FW, Stringham HM, Caronia RM, Johnson D, Abundo GP, Willcockson J, Downs CA, Thompson DA, Musarella MA, Gupta N, Othman MI, Torrez DM, Herman SB, Wong DJ, Higashi M, Boehnke M. Novel trabecular meshwork inducible glucocorticoid response mutation in an eight-generation juvenile-onset primary open-angle glaucoma pedigree. Ophthalmology 1998; 105:1698-707.
25. Wiggs JL, Allingham RR, Vollrath D, Jones KH, De La Paz M, Kern J, Patterson K, Babb VL, Del Bono EA, Broomer BW, Pericak-Vance MA, Haines JL. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. Am J Hum Genet 1998; 63:1549-52.
26. Yoon SJ, Kim HS, Moon JI, Lim JM, Joo CK. Mutations of the TIGR/MYOC gene in primary open-angle glaucoma in Korea. Am J Hum Genet 1999; 64:1775-8.
27. Suzuki R, Hattori Y, Okano K. Promoter mutations of myocilin gene in Japanese patients with open angle glaucoma including normal tension glaucoma. Br J Ophthalmol 2000; 84:1078.
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