WO2001088120A1 - Gene associe au glaucome a angle ouvert, y compris le glaucome a tension oculaire normale - Google Patents

Gene associe au glaucome a angle ouvert, y compris le glaucome a tension oculaire normale Download PDF

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Publication number
WO2001088120A1
WO2001088120A1 PCT/JP2001/004067 JP0104067W WO0188120A1 WO 2001088120 A1 WO2001088120 A1 WO 2001088120A1 JP 0104067 W JP0104067 W JP 0104067W WO 0188120 A1 WO0188120 A1 WO 0188120A1
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Prior art keywords
glaucoma
seq
gene
cytosine
thymine
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PCT/JP2001/004067
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English (en)
Japanese (ja)
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Yukio Hattori
Ryo Suzuki
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Tsubota Ltd.
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Priority to AU2001258753A priority Critical patent/AU2001258753A1/en
Publication of WO2001088120A1 publication Critical patent/WO2001088120A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to genes associated with open-angle glaucoma, including normal tension glaucoma.
  • the present invention further relates to a primer or probe for detecting a glaucoma-related gene, a kit for detecting a glaucoma-related gene, a glaucoma pre-onset diagnostic kit, and a method for preliminary detection of glaucoma.
  • Glaucoma is one of the major causes of blindness in Japan, Europe and the United States. In Japan, glaucoma including normal-tension glaucoma has been found in more than 3% of those aged 40 or older. Currently, about 200,000 people in Japan and about 800,000 worldwide have glaucoma.
  • Glaucoma In the statistics of developed countries as a whole, it is the second leading cause of blindness, and its proportion is increasing with aging (Quigley, HA ⁇ N. Engl. J. Med. 1998; 338: 1063- See 1064). Glaucoma generally occurs when the intraocular pressure is higher than the normal intraocular pressure, thereby impairing the blood circulation of the optic nerve tissue and causing optic nerve fibers to be exhausted, shed, and degenerated. Glaucoma is a serious eye disease that causes visual field abnormalities that can eventually lead to blindness. In Japan, normal tension glaucoma is characteristic, and there are more than three times as many patients as so-called high tension glaucoma.
  • P0AG primary open-angle glaucoma
  • This gene is located on the long arm of chromosome 1 and is reported as the juvenile open-angle glaucoma gene (GLCL1A). It encodes a 54 kd protein called myocilin (MYOC) (see Stone, EM et al., Science 1997; 275: 668-670).
  • the present inventors compared the nucleotide sequence of the promoter region of the myosin gene of a patient with open-angle glaucoma including normal-tension glaucoma with the nucleotide sequence of the corresponding portion of a healthy subject, and identified the promoter region of the patient with open-angle glaucoma. It was found that mutation occurred at a significant frequency at the position.
  • the gene according to the present invention is present in the promoter region of the myocillin gene, and has a remarkably high detection frequency in open-angle glaucoma including normal tension glaucoma.
  • the gene of the present invention is clearly different from the known mutations described above. Glaucoma often develops beyond the age of 40, but it is extremely difficult to make a definitive diagnosis early.
  • the glaucoma-related gene has a much higher frequency of occurrence in open-angle glaucoma including normal-tension glaucoma than the previously reported glaucoma-related gene.
  • the present invention relates to a polynucleotide comprising a DNA sequence represented by SEQ ID NO: 1, which is frequently present in open-angle glaucoma patients including normal-tension glaucoma in the promoter region of the myosin gene.
  • polynucleotide is used in a broad sense including what is generally called “oligonucleotide”.
  • the present invention relates to a polynucleotide in which thymine (T) at position ⁇ 153 in the DNA sequence upstream of the human myosilin gene represented by SEQ ID NO: 2 is substituted with cytosine (C).
  • T thymine
  • C cytosine
  • the present invention relates to a polynucleotide comprising a part or all of a nucleotide, wherein the polynucleotide comprises a base at least at position -153.
  • SEQ ID NO: 2 shows the nucleotide sequence at positions -473 to 3 of the human myocillin gene.
  • the positions of the bases are as follows: in the DNA, the translation start point is the first position, the adjacent base upstream thereof is the ⁇ 1 position, and n bases including the ⁇ 1 position base are upstream by n bases.
  • the position of the base located on the end side is called the 1 n-th position.
  • position -153 is located 153 bases upstream from the start of peptide synthesis; it is the position of the base in DNA.
  • T thymine
  • C cytosine
  • the present invention can include fragments of any length, if necessary, as long as they include the -153 position as well as those containing the entire upstream region of the myosillin gene.
  • a polynucleotide having a base length of 19 to 3 16 bp can be exemplified.
  • the present invention also relates to a primer used for amplifying the above-mentioned polynucleotide.
  • the primer those having any base length and sequence can be used as long as the target polynucleotide is amplified.
  • a primer of SEQ ID NO: 3 or SEQ ID NO: 6 can be used.
  • a set of primers consisting of the primer of SEQ ID NO: 3 and any of the primers of SEQ ID NOs: 4 to 6 can be used.
  • the present invention relates to a kit for detecting the substitution of thymine (T) to cytosine (C) at position ⁇ 153 of the promoter overnight region of the human myosillin gene, comprising the above primer. It can also provide kits containing such primers for diagnosing people who are more likely to develop glaucoma before developing glaucoma.These kits can be used to diagnose glaucoma, including normal tension glaucoma. If you are concerned about the disease, perform an auxiliary diagnosis for those who are concerned about the inheritance of the disease.
  • the present invention provides a probe represented by SEQ ID NO: 7, which is capable of detecting that the position at position -153 of the promoter region of the myosillin gene is cytosine (C), and a position at position -153 of the promoter region of the human myosillin gene.
  • a probe represented by SEQ ID NO: 8 which is capable of detecting thymine (T).
  • These probes have a 5 ' Those labeled with tin, fluorescent or 32 P are preferred. Using these probes, it is possible to distinguish between the thymine (T) and the cytosine (C) at position -153 of the promoter region of the human myosillin gene.
  • the present invention also provides a method for detecting the substitution of thymine (T) to cytosine (C) at position ⁇ 153 of the promoter region of the human myosillin gene, including the probes represented by SEQ ID NO: 7 and SEQ ID NO: 8.
  • T thymine
  • C cytosine
  • the kit for diagnosing a person who is likely to have glaucoma before developing glaucoma, comprising such a probe, can be provided.
  • kits provide an auxiliary diagnosis for those who are more likely to have open-angle glaucoma, including normotensive glaucoma.
  • the present invention provides a method for detecting glaucoma, which comprises detecting substitution of thymine (T) at position -153 with cytosine (C) in the DNA sequence of the promoter overnight region of the human myosillin gene. It relates to a method of detecting a highly likely person.
  • a mutation at the ⁇ 153 base in the promoter region of the myosillin gene can be detected.
  • the substitution of thymine (T) to cytosine (C) at the -153 base in the promoter region of the myosillin gene is not restricted to glaucoma, especially in normal tension glaucoma. It is closely related to angle glaucoma.
  • a presymptomatic diagnosis ie, future glaucoma
  • a presymptomatic diagnosis can be performed by examining whether the offspring or people in the family have a similar mutation. become.
  • the present invention relates to polynucleotides having a glaucoma-associated mutation.
  • Glaucoma that can be detected by the present invention includes normal-tension glaucoma and open-angle glaucoma.
  • the glaucoma-related gene of the present invention is, specifically, a polynucleotide comprising the DNA sequence represented by SEQ ID NO: 1, and a human represented by SEQ ID NO: 2
  • a polynucleotide comprising a part or the whole of a polynucleotide in which thymine (T) at position -153 in the DNA sequence upstream of the myosillin gene has been replaced by cytosine (C), wherein the polynucleotide comprises at least a base at position -153.
  • T thymine
  • C cytosine
  • the polynucleotide of the present invention includes a single-stranded DNA, a double-stranded DNA composed of a complementary strand thereof, and an antisense strand, and also includes a polynucleotide partially having a modified base. In addition, it includes those in which one or several bases are deleted, added or substituted at positions other than -153.
  • Such a polynucleotide is one of the genes responsible for glaucoma, especially normal tension glaucoma and open angle glaucoma. Therefore, primers, probes and kits for testing for the presence or absence of such a polynucleotide should be used in glandular diagnosis and glaucoma patients, and in genetic diagnosis for glaucoma progeny. Can be used.
  • the primer of the present invention is not particularly limited as long as it is a primer pair substantially complementary to a part of the upstream and downstream sequences at position ⁇ 153 of the myosillin gene.
  • substantially complementary means that it is only necessary to be complementary enough to be able to anneal to the upstream and downstream sequences at position ⁇ 153 of the myosillin gene.
  • a primer containing a sequence that is not complementary to a part of the myosillin gene at the 5 'end, or at the 3' end, or at both the 5 'end and the 3' end of the primer as long as it can anneal to the myosillin gene. It is to be included in the primer of the present invention.
  • a primer having a mismatch sequence that is not complementary to the myosillin gene can be used.
  • Suitable primers include one or more primers of SEQ ID NO: 3 to SEQ ID NO: 6. Using a pair of primers consisting of the primer of SEQ ID NO: 3 and any one of SEQ ID NOs: 4 to 6, a polynucleotide containing the -153 position of the myosillin gene can be amplified by PCR or the like. .
  • the method for detecting the substitution of thymine (T) at position -153 of the myosin gene with cytosine (C) is not particularly limited.
  • the detection is performed by determining the base sequence by the Sanger method or the like.
  • RFLP Restriction Fragment Length As in the case of Polymorphism
  • Restriction enzymes that can be used for RFLP include SinaI.
  • PCR Polymerase Chain Reaction
  • PCR-RFLP PCR-Restriction Fragment Length Length
  • PCR-SS0 PGR-Specific Sequence
  • Oligonucleotide PCR-SSCP (PCR-Single Strand Conformation Polymorphism analysis)
  • allele-specific PCR allele-specific PCR
  • thymine (T) substitution of thymine (T) to cytosine (C) at position ⁇ 153 of the myosin gene is detected by dot blot hybridization using the probe of the present invention.
  • the probe of SEQ ID NO: 7 allows detection of the myosin gene whose position at position -153 is cytosine (C)
  • the probe of SEQ ID NO: 8 allows detection of the myosillin gene whose position of -153 is thymine (T).
  • a primer is added to the reaction buffer containing dNTP, and a thermostable DNA polymerase is further added. The cycle of denaturation, annealing, and extension is repeated to amplify the myosin gene containing position -153.
  • the reaction buffer is, for example, 10 mM Tris-Cl (pH 8.9), 1.5 mM MgCl2, 80 mM KC1, 0.5 mg / ml BSA, 0.1% sodium cholate (0.1%).
  • a buffer containing Triton X-100 can be used. However, the present invention is not limited to this reaction buffer, and any reaction buffer can be used.
  • the denaturation, annealing, and extension cycle is typically 30 seconds to 1 minute 30 seconds at 94 ° C for denaturation, 30 seconds to 1 minute 30 seconds at 55-68 ° C for annealing, and 72 ° C for extension. 25 to 40 cycles are performed in 30 seconds to 5 minutes, but the invention is not limited to this range.
  • denaturation can be performed at 94 ° C for 1 minute, annealing at 62 ° C for 1 minute, and extension at 72 ° C for 2 minutes for 25 to 40 cycles.
  • a commercially available thermostable polymerase such as Taq polymerase or Tth polymerase can be used.
  • the primer can use a primer pair that is substantially complementary to a portion of the sequence upstream and downstream of position -153 of the myosillin gene, as previously described.
  • Those skilled in the art will appropriately select the reaction buffer, reaction conditions, and primers according to the length of the primers used, the complementarity of the primers, or the various PCR modifications described below. Only the sequence can be amplified.
  • primers used for PCR-SSCP primers of SEQ ID NO: 3 and SEQ ID NO: 4 can be used.
  • the resulting 185 bp PCR fragment contains the myosillin gene in which the position -153 is substituted with thymine (T) for cytosine (C).
  • T thymine
  • C cytosine
  • the positions -154 to -149 are CCCGGG
  • the positions of -153 to -149 are CTCGGG for the myosin gene without substitution at position -153. Since only the sequence of CCCGGG is recognized and cleaved by the restriction enzyme Smal, treatment of the 185 bp fragment after PCR containing CCCGGG with Smal will generate a 163 bp fragment and a 22 bp fragment.
  • the 185 bp fragment after PCR was treated with Smal, and the presence or absence of the 163 bp fragment was detected by polyacrylamide gel electrophoresis or agarose gel electrophoresis. It can be determined whether or not it has been replaced with cytosine (C).
  • one primer - 153 of the designed such portions that correspond comes 3 3 terminus, thymine (T) at position -153 mustard
  • T thymine
  • C tosin
  • An example of such a set of primers is the primers of SEQ ID NO: 3 and SEQ ID NO: 6.
  • the primer of SEQ ID NO: 6 is used at the 3 'end of the primer to prevent nonspecific growth. There is a mismatch with cytosine (C) at the fourth base from adenine (A).
  • adenine A
  • nested PCR that is, a sequence, under strict PCR conditions, so that only those in which position -153 is substituted with cytosine (C) are amplified.
  • the fragment amplified by PCR using the primers of No. 3 and SEQ ID No. 4 is preferably subjected to PCR using the primers of No. 3 and No. 6 as type III.
  • the PCR fragment containing the -153 position amplified using SEQ ID NO: 3 and SEQ ID NO: 4 is spotted on a nylon membrane or the like after denaturation.
  • a prehybridization buffer eg, containing 5x Denhardt's solution (Denhardt, s), 5x SS 0.1% SDS, 0.1mg / ml denatured dicin sperm DNA
  • 5x SS 0.1% SDS 0.1% SDS
  • SEQ ID NO: 7 labeled SEQ ID NO: 8 was added at etc. fluorescence, further Inkyube over preparative.
  • the hybridization temperature may be about 40 hours to about 50 degrees Celsius for about 2 hours, and tetramethylammonium chloride may be used for washing.
  • the kit of the present invention includes a primer capable of amplifying the promoter region of the myosinillin gene including position -153 of the myosillin gene or a probe capable of specifically hybridizing by distinguishing the difference in the base at position -153.
  • a reagent included in the kit Can be appropriately changed by a method for detecting base substitution. For example, when the nucleotide sequence is determined by the Sanger method, ddATP, ddTTP, ddCTP, ddGTP and dATP, dTTP, dCTP, dGTP, DNA synthase, etc. are included in addition to the primers.
  • an appropriate restriction enzyme for example, one containing Smal can be mentioned.
  • the kit of the present invention comprises a buffer and a washing solution suitable for detecting the substitution of thymine (T) for cytosine (C) at position -153 of the promoter region of the human myosillin gene. Is also good.
  • the glaucoma pre-onset diagnostic kit of the present invention is for detecting the substitution of thymine (T) for cytosine (C) at position ⁇ 153 of the promoter region of the human myosillin gene. As an active ingredient.
  • the glaucoma pre-onset diagnosis kit of the present invention is useful for early detection and treatment of glaucoma.
  • the DNA whose presence or absence of substitution is detected by the present invention can be obtained from human hair, blood, body fluid, saliva, cultured cells, excised tissue, and the like, and is not particularly limited.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
  • the following first and second surveys were conducted on Japanese patients with open-angle glaucoma, including normal-tension glaucoma.
  • the subjects of the examination were 83 patients with open-angle glaucoma, including normal-tension glaucoma, who had a total family history of glaucoma, and healthy subjects who were considered to have no eye disease because they had not visited an ophthalmology department 101 people. Both groups have similar structures such as age.
  • Nal method Wang Lli et al: Purification of genomic DNA from human whole blood by isopropanol -fractionation with concentrated Nal and SDS. Nucleic Acid Res., 22: 1774-) from 83 peripheral blood leukocytes of patients with glaucoma (P0AG) 1775, 1994).
  • 101 abnormal healthy subjects were analyzed for the same gene abnormality.
  • Information on the normal nucleotide sequence of the myocillin gene was obtained from GenBank accession numbers AB006686, AB006686S2, AB006686S3.
  • the amplified fragment (185 bp) obtained by nested PCR was purified by alcohol precipitation, and then hydrolyzed with SmaI (Toyobo, Osaka, Japan) at 37 ° C for 6 hours. Thereafter, 8% polyacrylamide gel electrophoresis was performed in a pH 8.3 buffer solution of 0.114 M tris-boric acid (containing 2 mM EDTA), and cytosine (C) at position ⁇ 153 was obtained by staining with bromide chidium. Was searched for the presence or absence of a 163 bp fragment specific to the sequence that was replaced.
  • the second abnormality was a new mutation in the GT repeat at positions -339 to -314. These are considered to be statistically polymorphic.
  • This mutation was detected in a very large number of patients, about 20% of open-angle glaucoma, including normotensive glaucoma. This high frequency is a remarkable figure in genetic studies as a single disease-related mutation. Since the history of this discovery was the most important motivation for applying for a patent for the present invention, the details will be described below in accordance with experiments. As shown in the table, in the first survey, this gene was found in 17% of glaucoma, but in the control group, mutation was found in 7.9%. There was no significant difference.
  • the combined mutations in the first and second surveys were 16 in the patient group and 6 in the control group. It is not known whether glaucoma or glaucoma is present in the second group of controls since the third group had not performed an ophthalmic examination. However, a total of 19 in the first survey, where a substitution of thymine (T) for cytosine (C) was detected at position -153, and 11 in the patient group in the second survey, a total of 19 The person had normal tension glaucoma or open angle glaucoma. Patients were characterized by the fact that most had a maximum intraocular pressure of 30 mmHg or less.
  • -83G ⁇ A means substitution of guanine (G) to adenine (A) at position -83, and n in the column of (GT) n represents the number of repeats of GT.
  • -153T ⁇ C means substitution of thymine (T) to cytosine (C) at position -153.
  • GT n is statistically polymorphic. From the results in the table, the mutation of thymine (T) to cytosine (C) at position -153 is clearly associated with glaucoma. This mutation was also commonly found in the first survey, the second survey and in total, in about 20% of patients with open-angle glaucoma.
  • promoter activity is clearly different for the thymine (T) and cytosine (C) alleles at position -153, and that the change in promoter activity is due to the GT nucleotide 160 nucleotides upstream of this mutation. It was suggested that it is related to the linkage between the number of dinucleotide repetitions and.
  • This allele at position -153 was first discovered in our study and is the major mutation associated with open-angle glaucoma, including normotensive glaucoma. This gene is significantly more frequent than previous reports of normal tension glaucoma and juvenile open angle glaucoma.
  • the gene of the present invention can be used for screening when the onset cannot be detected clinically. Is also useful.
  • a glaucoma patient can be detected at an early stage, and the person who is highly likely to suffer from glaucoma can be detected with high accuracy not reported in the conventional gene.
  • genetic diagnosis is possible for the first time for normal-tension glaucoma with a large number of patients and few subjective symptoms.
  • groups with a high likelihood of glaucoma in families can be detected.
  • the glaucoma-related gene of the present application can be obtained using the glaucoma diagnosis kit or method of the present invention, if desired, even if the onset cannot be confirmed ophthalmologically. It is also valuable because it can be tested for the presence of a glaucoma and whether the trait associated with glaucoma is inherited.

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Abstract

L'invention concerne des polynucléotides à substitution de thymine (T) par la cytosine (C) en position -153 du gène de la myociline, lesdits polynucléotides étant identifiés comme un gène associé au glaucome. Pour déceler ces polynucléotides, on peut utiliser les amorces des séquences SEQ ID NOS: 3 à 6 et les sondes des séquences SEQ ID NOS: 7 et 8. L'invention concerne également des kits reposant sur l'utilisation des amorces propres aux séquences SEQ ID NOS: 3 à 6 et des sondes propres aux séquences SEQ ID NOS: 7 et 8. L'utilisation de ces kits permet de déceler le glaucome à tension oculaire normale et le glaucome à angle ouvert selon une fréquence largement supérieure à celle qui caractérise la détection de ce type d'affection par le biais des gènes associés au glaucome déjà connus. Par ailleurs, les kits décrits sont utilisables pour le dépistage du glaucome chez les patients pour lesquels on redoute le glaucome héréditaire ou bien les porteurs asymptomatiques. En outre, pour la première fois, il devient possible de diagnostiquer le glaucome à angle ouvert avant la survenue de l'affection, y compris le glaucome à tension oculaire normale.
PCT/JP2001/004067 2000-05-17 2001-05-16 Gene associe au glaucome a angle ouvert, y compris le glaucome a tension oculaire normale WO2001088120A1 (fr)

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AU2001258753A AU2001258753A1 (en) 2000-05-17 2001-05-16 Gene associating open-angle glaucoma including normal ocular tension glaucoma

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JP2000144492A JP2002306165A (ja) 2000-05-17 2000-05-17 正常眼圧緑内障を含む開放隅角緑内障の関連遺伝子
JP2000-144492 2000-05-17

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JPWO2008130008A1 (ja) 2007-04-17 2010-07-22 木下　茂 緑内障発症リスクの判定方法
NZ582131A (en) * 2007-06-13 2012-07-27 Decode Genetics Ehf Genetic variants on chr 15q24 as markers for use in diagnosis, prognosis and treatment of exfoliation syndrome and glaucoma
JP7202609B2 (ja) * 2017-12-13 2023-01-12 国立大学法人東北大学 視神経障害の診断用バイオマーカー
CN109694911B (zh) * 2018-12-17 2022-05-27 四川省人民医院 一种原发性开角型青光眼的筛查试剂盒

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1998032850A1 (fr) * 1997-01-28 1998-07-30 The Regents Of The University Of California Dispositif d'interface informatique pour ecran a plasma de type ca
WO1999051779A2 (fr) * 1998-04-07 1999-10-14 The University Of Iowa Research Foundation Traitement et diagnostic du glaucome
WO2000042220A1 (fr) * 1999-01-11 2000-07-20 The Regents Of The University Of California Acides nucleiques, kits, et methodes de diagnostic, de pronostic, et de traitement du glaucome et des troubles associes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998032850A1 (fr) * 1997-01-28 1998-07-30 The Regents Of The University Of California Dispositif d'interface informatique pour ecran a plasma de type ca
WO1999051779A2 (fr) * 1998-04-07 1999-10-14 The University Of Iowa Research Foundation Traitement et diagnostic du glaucome
WO2000042220A1 (fr) * 1999-01-11 2000-07-20 The Regents Of The University Of California Acides nucleiques, kits, et methodes de diagnostic, de pronostic, et de traitement du glaucome et des troubles associes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DILIANA S. ET AL.: "Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma", J. MED. GENET., vol. 35, 1998, pages 989 - 992, XP002946917 *
SUZUKI R. ET AL.: "Promoter mutations of myocilin gene in Japanese patients with open angle glaucoma including normal tension glaucoma", BR. J. OPHTHALMOL., vol. 84, no. 9, September 2000 (2000-09-01), pages 1078, XP002946916 *

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