Human Molecular Genetics, 2000, Vol. 9, No. 3 367-374
© 2000 Oxford University Press
Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus
Departments of 1Molecular and Human Genetics, 2Ophthalmology, 3Medicine and 4Pediatrics, Baylor College of Medicine, Houston, TX, USA, 5The Texas Children’s Hospital, Houston, TX, USA and 6King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
Received 24 September 1999; Revised and Accepted 1 December 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Primary congenital glaucoma (PCG) is an autosomal recessive disorder associated with unknown developmental defect(s) in the anterior chamber. Recently, we reported three distinct mutations in CYP1B1, the gene for cytochrome P4501B1, in 25 Saudi families segregating PCG. For this report, we analyzed 37 additional families and confirmed the initial finding of decreased penetrance. Mutations and intragenic single-nucleotide polymorphisms (SNPs) were also analyzed from direct sequencing of all CYP1B1 coding exons. Eight distinct mutations were identified: G61E, R469W and D374N, the most common Saudi mutations, account for 72, 12 and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (two deletions and three missense mutations) were detected, each in a single family. Affected individuals from five families had no CYP1B1 coding mutations, and each family had a unique SNP profile. The identification of eight distinct mutations in a single gene, on four distinct haplotypes, suggests a relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia. These data demonstrate decreased penetrance of the PCG phenotype in the Saudi population, because 40 apparently unaffected individuals in 22 families have mutations and haplotypes identical to their affected siblings. Two individuals were subsequently diagnosed with glaucoma and two others had abnormal ocular findings that are consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggests the presence of a dominant modifier locus that is not linked genetically to CYP1B1. Linkage and Southern analyses excluded three candidate modifier loci.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Primary congenital glaucoma (PCG; MIM 231300) is a devastating autosomal recessive disorder that is associated with developmental defect(s) of the anterior chamber (1). The disease occurs when the intraocular pressure (IOP) is increased, leading to an enlarged cornea, and eventually to optic nerve damage. Discrimination of affected from unaffected siblings is not difficult, especially in populations in which a relative delay in care may occur due to geographical or social circumstances. Medical treatment has limited value. Although PCG is the most common form of glaucoma in infancy, it is uncommon in the North American population (<1 in 30 000), where no population isolates are known. In Saudi Arabia, however, it is a more common condition, with an estimated incidence of 1 in 2500 liveborns, often in offspring of consanguineous marriages (2–4). Indeed, PCG is the most common cause of childhood blindness in the Kingdom of Saudi Arabia.
A PCG locus (GLC3A) was linked to markers on the short arm of chromosome 2 in 11 Turkish families (1) and mutations in CYP1B1, the gene for cytochrome P4501B1, were described in three Turkish families (2). The localization of GLC3A to 2p21 was confirmed by linkage analysis in 25 Saudi Arabian families, and three distinct disease-associated missense mutations in CYP1B1 were described in 24 of these 25 families (4). The identification of 11 clinically unaffected individuals with both haplotypes and mutations identical to their affected siblings was a novel finding (4). These data suggested decreased penetrance for the phenotype in this population. More recent studies in outbred North American and European pedigrees and in inbred Turkish and Gypsy families identified additional mutations in CYP1B1, but showed no evidence for less than complete penetrance (3,5).
We have now analyzed the coding region of CYP1B1 in 37 additional Saudi PCG families (Fig. 1) together with the cohort of 25 previous pedigrees (4,6). These studies reveal multiple independent disease-associated mutations in CYP1B1 and confirm our earlier observation of incomplete penetrance. Our observations suggest that a major modifier locus is present in the Saudi population and that this locus is dominant. Simulation studies show that the Saudi cohort provides enough information to map this modifier. We have excluded three candidate loci by linkage and Southern blot analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutation analysis
DNA from all affected individuals and their parents (obligate carriers) was analyzed by polymerase chain reaction (PCR) amplification of the coding region of CYP1B1, followed by either enzyme digestion or sequencing of the amplification products. A total of eight distinct mutations were detected in 57 of the 62 families (Table 1). Of these, five different transitions and one transversion (8005C
A) that, by conceptual translation, result in missense amino acid substitutions were found in 55 families. Three of these single amino acid substitutions (G61E, R469W and D374N) account for the majority (92%) of the CYP1B1 mutations in Saudi Arabia. Only four families showed compound heterozygous affected individuals, two for each of G61E/R469W and G61E/D374N (Table 1). In addition, two deletions were detected: (i) a 10 bp deletion at nucleotide 4238 that, by conceptual translation, results in a shift of the reading frame, causing a premature stop two amino acids downstream of the deletion; this is the only presumptive null mutation in this cohort; and (ii) a 9 bp deletion that is predicted to cause the loss of three amino acids (Ser-Asn-Phe) from the middle of the putative protein, without shifting the reading frame (Table 1). All mutant alleles co-segregate with the disease phenotype. None of these eight alterations were detected in the 100 unrelated Saudi control chromosomes (data not shown). No mutations in CYP1B1 coding exons were detected in five PCG families (Table 2).
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Segregation of mutations in families
Our initial report of decreased penetrance of the glaucoma phenotype was confirmed by either restriction enzyme analysis or sequencing of all available clinically unaffected at-risk individuals. Forty individuals in a subgroup of 22 families were found to have ‘affected’ genotypes, but were clinically unaffected at the time of enrollment in the study. Each one of these individuals was either homozygous or compound heterozygous for mutations in CYP1B1 (Fig. 2). A total of 108 individuals were affected both clinically and genotypically in the 57 families investigated. Based on these data, the penetrance in this cohort of 57 families is 108/148, or 0.73.
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Of the 57 pedigrees studied, 35 families showed complete penetrance whereas 22 families did not. The 22 families had 38 subjects with classic PCG caused by CYP1B1 mutations, whereas 40 individuals demonstrated non-penetrance (Fig. 2). Thus, in this subset of 22 pedigrees approximately half of the individuals with the ‘affected’ genotypes are non-penetrant [40 out of (40 + 38)]. If one assumes the presence of a single Mendelian modifier locus causing the non-penetrance, then the expectations are that a rare dominant locus would result in 50% of individuals with the ‘affected’ genotype being clinically unaffected. In contrast, a rare recessive locus would be expected to result in the lower percentage of 25%. The absence of gender bias in these non-penetrant individuals makes an X-linked modifier locus unlikely. The observed ratio in these 22 families (40/78 = 0.51) is in complete agreement with the prediction of the dominant model. The non-penetrant phenotype was observed in families who were homozygous or compound heterozygous for missense mutations (G61E, R469W and R368H homozygotes; G61E/R469W and G61E/D374N compound heterozygotes) and in the single family with the frameshift deletion that is predicted to result in premature termination of the CYP1B1 polypeptide (KKECG-106) (Table 1; Fig. 2). Interestingly, non-penetrance was also detected in a parent (KKECG-165)
Updated clinical information was sought on the clinically unaffected individuals who were shown to have ‘affected genotypes’. Initial telephone interviews identified two individuals (KKECG-123-06 and KKECG-151-05) who, by their parents’ report, were diagnosed with glaucoma a few years following their enrollment. These individuals were not re-examined. Seven other individuals, however, were evaluated thoroughly at the King Khaled Eye Specialist Hospital (KKESH) or at their homes (KKECG-137-10, -137-12, -137-13, -114-04, -113-09, -113-13 and -170-05) (Fig. 2). None of these patients had the characteristic optic nerve changes of glaucoma. However, KKECG-137-12 showed asymmetrical IOP at 16 years. KKECG-113-13 had findings suggestive of glaucoma with elevated IOP, enlarged and asymmetrical corneas, and minimal cupping of the optic disks at 6 years. There is no evidence for an increased incidence of adult-onset primary open angle glaucoma or any other disease in the individuals carrying two mutations that demonstrate non-penetrance.
Single-nucleotide polymorphism and haplotype analyses
Analysis of 48 unrelated and unaffected Saudi controls identified six single-nucleotide polymorphisms (SNPs) in CYP1B1, but none of the disease-associated mutations described herein (data not shown). These SNPs have also been found in Turkish and British controls (3) and in North American subjects (7), and have been catalogued by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/cyp1b1.htm ). Haplotypes constructed with these SNPs showed a common ‘PCG haplotype’ in this cohort (Table 1). This common haplotype (C/C/G/G/T/A) occurs in 94.7% of the Saudi PCG chromosomes. The assignment of mutations to these haplotypes shows that five distinct mutations occurred on the same common haplotype. Three other independent mutations were found on distinct haplotypes. Distinct haplotypes were detected in four of the five families who had no mutations detected in the coding region of CYP1B1. The heterozygous haplotypes in three of these consanguineous families do not show identity-by-descent inheritance and therefore suggest that PCG is not linked to GLC3A on 2p21 (Table 2).
Mapping the modifier locus and the exclusion of candidates
Simulation analysis evaluated the power of the pedigrees with non-penetrance to detect a single locus that determines the PCG status (affected/penetrant versus unaffected/non-penetrant) in the presence of homozygous or compound heterozygous CYP1B1 mutations. Simulations were performed with four models of modifier locus effect. These included combinations of autosomal dominant versus recessive, and protective versus liability effects. Given the uniqueness of the Saudi Arabian population for non-penetrance, high degree of consanguinity and relative genetic homogeneity, we assumed a single modifier locus. The SIMLINK computer program predicts the ability to detect the locus with a high degree of confidence with a four-allele system and 95% penetrance of the modifier locus. As an example, for the model of a dominant protective modifier segregating in the 22 pedigrees containing non-penetrant individuals, it is predicted that the maximum achievable Lod scores are 22.0 for 
= 0.00, 21.8 for = 0.05 and 21.6 for = 0.15. This analysis simulates the genotypes for the DNA samples collected and performs a two-point analysis. The data are not shown for the other three models (dominant susceptibility, recessive protective and recessive susceptibility). Alternatively, it is also possible that multiple modifiers exist in this population. Some of these could be environmental, others genetic. Serendipitous interaction of such modifiers in this population could have resulted in full penetrance in ~50% of mutation-bearing individuals.
Parametric analysis tested linkage of the penetrant or non-penetrant phenotype with simple sequence repeat polymorphisms linked to candidate loci. Three candidate loci were evaluated [the aryl hydrocarbon receptor locus (AhR) on 7p15, the aryl hydrocarbon nuclear translocator locus (ARNT) on 1q21 and a cytochrome P450 locus (CYP2D6) on 22q13], either because of their putative role in modulating CYP1B1 expression (AhR and ARNT) (8) or because of a common genomic rearrangement unique to the Saudi population (CYP2D6) (9). Two-point linkage analyses excluded each of these candidate loci (Fig. 3; data not shown). Furthermore, Southern analysis to visualize directly the common duplication mutations at the CYP2D6 locus showed no evidence of CYP2D6 duplication in any of the EcoRI-digested genomic DNA from clinically affected and non-penetrant individuals (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutational analyses of CYP1B1 coding exons showed homozygous mutations in 53 of 62 Saudi Arabian PCG families. Four families showed compound heterozygous affected individuals and five families had no mutations in CYP1B1 coding exons (Table 1). In each family in which mutations were detected, the mutant alleles co-segregate with the disease phenotype in an autosomal recessive pattern. Six distinct missense mutations were defined in these 57 families. Each of the six mutated amino acid residues is highly conserved (Fig. 4). Three of these mutations occurred at a CpG dinucleotide (8242C
T, 7940GA, 8005CA).
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SNP analysis reveals a common haplotype (C/C/G/G/T/A) that is associated with five distinct mutations in 94.7% of the Saudi PCG chromosomes. At least three possible hypotheses could explain these findings. (i) The common haplotype is the oldest in the Saudi population, and the three most common mutations occurred independently, but shortly after the founding of the Saudi population. The remaining five mutations occurred much more recently, after some divergence from the founding haplotype. (ii) This distinctive haplotype (C/C/G/G/T/A) is the most common in the Saudi population and, as such, is much more likely to be the target of random mutational events. (iii) This haplotype causes conformational changes in the DNA that would predispose to mutations or would make the DNA at that locus less accessible to repair enzymes.
The first scenario is favored because it explains both the high number of independent mutations in this inbred and genetically isolated population, and the high prevalence of the disease with the historical reality of a few founders for the Kingdom of Saudi Arabia. Furthermore, the frequency of the common haplotype in the general Saudi population supports this conclusion. This frequency was estimated by assuming that the control Saudi population is in Hardy–Weinberg equilibrium (p2 + 2pq + q2 = 1), by identifying individuals homozygous for the C/C/G/G/T/A haplotype, and inferring the frequency of the haplotype. Forty-eight control individuals were analyzed, six of whom were found to be homozygous (q2) for the C/C/G/G/T/A haplotype. Thus, the inferred haplotype frequency is 0.35 in the Saudi population (q). These data do not suggest an overwhelming frequency of this haplotype in the general Saudi population and provide further support for the conclusion that the mutations occurred at or around the settling of the Arabian Peninsula, with a founder effect.
Similar findings have been reported in Druze and Muslim populations segregating Hurler syndrome and metachromatic leukodystrophy in the Lower Galilee (10,11). A historically more recent genetic isolate segregating limb girdle muscular dystrophy in the island of La Réunion was also found to have multiple mutations on different haplotypes, despite the expectation of a single founder mutation (12,13). The alternative hypotheses of a high mutation rate with heterozygous advantage or of a digenic inheritance have been proposed to explain these observations in La Réunion (14,15). Our data from this Saudi population suggest that the most likely model is a relatively recent occurrence of several mutations in CYP1B1, coupled with an unlinked dominant modifier.
Historical data suggest that the early inhabitants of the Arabian Peninsula formed a genetic isolate that was established by relatively few founders. Their descendants then established various tribes that dispersed across the Kingdom. Therefore, the majority of native Saudi Arabians living today have common ancestors. In a population with a high coefficient of inbreeding and multiple offspring, the occurrence of mutations in a single gene will lead to a clinical phenotype within four or five generations of the occurrence of each of these mutations by virtue of identity-by-descent inheritance. Furthermore, the finding of eight distinct mutations is consistent with the recent studies suggesting that the incidence of new mutations is a common phenomenon (16). Thus, it is likely that some unique qualities of this population or its environment allowed the propagation of these mutations by a founder effect and genetic drift (14).
The finding of incomplete penetrance of the PCG phenotype in this population is both novel and unique. Although variable expressivity of the PCG phenotype has been suggested in the clinical literature (17), no molecular studies document decreased penetrance in any other PCG cohorts reported to date (3,18). Some of these populations share some of the same mutations (e.g. G61E and R469W) that exhibit non-penetrance in our population. Analysis of the 22 pedigrees that manifest decreased penetrance suggests the presence of a dominant suppressor of the PCG phenotype that is not linked genetically to CYP1B1. The co-inheritance of homozygous or compound heterozygous CYP1B1 mutations and this putative dominant modifier seems to confer protection from the severe phenotype. Interestingly, the effects of both missense mutant alleles and a presumably null frameshift allele were suppressed.
Without a known advantage to carriers of CYP1B1 mutations, the combination of decreased penetrance, multiple independent mutations in a single gene and the suggestion of a single modifier locus is unique. This may be the first example in Homo sapiens of a suppressor that contributes to the propagation of recessive deleterious alleles. The role of modifiers of recessive deleterious or lethal alleles in maintaining a high frequency of these alleles in inbred Drosophila colonies is well documented (19,20). Indeed, these suppressors are useful in the cloning of lethal alleles. In H.sapiens, however, the documentation of selection for such modifiers is less direct. Hemoglobin gene mutations are perhaps an example, in which deletions in the 
-globin genes on chromosome 16 causing -thalassemia act as modifiers of the sickle phenotype in homozygotes for mutations in the ß-globin gene on chromosome 11 (21,22). The apparent active selection for either the -globin gene deletions or the sickle mutation in such populations, however, is thought to be due to the protective effect of these alterations against malaria, rather than a direct suppressor effect.
Sequence variation in several candidate loci such as AhR and ARNT, each of which acts as a transcriptional activator of a number of cytochrome genes including CYP1B1 (23), potentially could explain the phenotypic variation in this population and could direct a targeted medical therapy in this condition. Other candidate loci that might suppress the PCG phenotype include other cytochrome P450 enzymes that share substrates with CYP1B1. It is possible that other cytochrome gene poly- morphisms unique to the Saudi population compensate for the enzymatic deficiency of CYP1B1. For example, 20% of the Saudi population has a duplication of CYP2D6 on 22q13 (9). This genotype results in an ultrarapid metabolizing phenotype. The frequency of this phenotype seems to be unique to the Saudi and Ethiopian populations (9). Each one of these three candidates was excluded as a possible modifier by linkage analysis with markers that span each of the loci. Furthermore, a duplication of CYP2D6 that could have been missed by linkage analysis alone was excluded by Southern analysis. Other cytochrome genes (e.g. CYP1A1 and CYP1A2) or other glaucoma loci could also be considered as possible modifier candidates of the PCG phenotype.
The study of genetic isolates and inbred populations represents an important strategy to map Mendelian traits rapidly and to dissect complex human disorders. The inherent mutational diversity in these isolates is often under-appreciated when studying such populations for homozygosity mapping or linkage disequilibrium. Our findings also illustrate the power of these populations to identify and possibly to map candidate modifier genes. The cloning of such a modifier gene should substantively impact our understanding of the pathogenesis of congenital glaucoma and the identity of the physiological substrate(s) of CYP1B1.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Subjects
Sixty-two Saudi PCG families have been ascertained and enrolled into a genetic research program through either the Glaucoma or the Pediatric Ophthalmology Clinics at KKESH (Riyadh, Saudi Arabia). KKESH serves as the tertiary eye care center for the Kingdom. Thus, patients seen at this institution are referred from diverse rural and urban areas, and are representative of the Saudi population. The ophthalmological information for each individual was scored as affected or unaffected by one of three investigators (K.F.T., W.F.A. and D.K.D.) and was reviewed independently by another (R.A.L.), none of whom had prior knowledge of data on any linkage or mutation. Other recognized systemic associations or combinations of infantile glaucoma were excluded carefully. Within each kindred, a detailed family history and pedigree were obtained through personal interviews (R.A.L. and M.J.) with appropriate relatives. Ascertainment of families was designed for the positional cloning of the PCG gene. Thus, families with two or more affected individuals with living parents were sampled preferentially. Each subject, or the responsible adult on behalf of minors, signed a consent form for participation in these investigations, which was approved by the Baylor Affiliates Review Board for Human Subject Research and the parallel committees at KKESH.
Initially, a panel of 25 families informative for the design and objectives of this study was selected. These families have been described in detail elsewhere (6). This report details studies of both these and additional 37 families (Fig. 1).
Individuals who were assigned ‘unaffected’ clinical status on initial enrollment, but who had an ‘affected’ haplotype because of homozygous or compound heterozygous mutations in CYP1B1, were contacted by telephone. Formal ophthalmological evaluations were then scheduled at KKESH or at the subjects’ homes. Fifty unrelated native Saudi Arabian adults with no family history of hereditary eye disease were used as a control population for mutational studies of CYP1B1 and 48 for identification of SNPs. These individuals were seen at KKESH for conditions unrelated to any hereditary eye disease.
CYP1B1 mutation testing
CYP1B1 (GenBank accession no. U56438) coding exons 2 and 3 were each sequenced following PCR amplification (4). The presence of G61E was also tested by TaqI digestion and agarose gel electrophoresis of amplified DNA from exon 2; individuals with homozygous G61E mutations detected by restriction digests were then confirmed by sequence analyses.
SNP analysis
Analysis of sequence variation in control, carrier and affected individuals was recorded. PCG haplotypes were constructed with these intragenic polymorphisms in affected individuals.
Markers and linkage analysis
ABI PrismLinkage Mapping Set markers (PE Applied Biosystems, Foster City, CA) were used to investigate linkage of the modifier locus to each of AhR (D7S513, D7S507, D7S493), ARNT (D1S2726, D1S252, D1S498, D1S484) and CYP2D6 (D22S280, D22S283, D22S423, D22S274). Amplification, gel electrophoresis and data analysis were performed according to manufacturer’s recommendations.
Linkage analysis was carried out with the FASTLINK software package (v4.0P) (24–28). Equal allele frequencies were assumed for the marker alleles and an allele count equal to the number of alleles observed in the pedigrees genotyped. Nearly complete (95%) protection (or liability) of the modifier and an allele frequency of 20% were used.
Southern analysis
CYP2D6 cDNA was kindly provided by Dr F. Gonzalez (National Institutes of Health, Bethesda, MD). EcoRI digestion was performed on 4 µg of genomic DNA from clinically affected and non-penetrant individuals. (29).
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ACKNOWLEDGEMENTS |
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Sincere appreciation is extended to the families for their willing and continuing cooperation in these investigations. The authors gratefully acknowledge the attending physicians, the Director of Research Ali Al-Rajhi and the staff of the Research Department at King Khaled Eye Specialist Hospital (Riyadh, Saudi Arabia), for their identification and accession of these families. Genotyping was performed at the Kleberg Genotyping Center at Baylor College of Medicine. R.A.L. is a Senior Research Scientist of Research to Prevent Blindness (RPB). This work was supported in part by grants from the National Eye Institute Mentored Clinical Scientist Development Award (K23 EY00370) (B.A.B.) and (K23 EY00375) (D.W.S.); National Eye Institute R01 EY11780 (J.R.L. and R.A.L.); Baylor College of Medicine Child Health Research Center (B.A.B.); National Glaucoma Research, a program of the American Health Assistance Foundation (Rockville, MD) (R.A.L.); Research to Prevent Blindness, Inc. (New York, NY) (R.A.L.); the Kleberg Foundation.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM 225, Houston, TX 77030, USA. Tel: +1 713 798 6871; Fax: +1 713 798 5073; Email: bbejjani@bcm.tmc.edu
§ Present address: Beirut Eye Specialist Center, Rizk Hospital, Beirut, Lebanon
¶ Present address: Eye Clinic, Alberta Children’s Hospital, Calgary, Alberta, Canada
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REFERENCES |
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S. Chakrabarti, K. R. Devi, S. Komatireddy, K. Kaur, R. S. Parikh, A. K. Mandal, G. Chandrasekhar, and R. Thomas Glaucoma-Associated CYP1B1 Mutations Share Similar Haplotype Backgrounds in POAG and PACG Phenotypes Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5439 - 5444. [Abstract] [Full Text] [PDF]
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J. L. Wiggs Genetic Etiologies of Glaucoma Arch Ophthalmol, January 1, 2007; 125(1): 30 - 37. [Abstract] [Full Text] [PDF]
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C. Bidinost, N. Hernandez, D. P. Edward, A. Al-Rajhi, R. A. Lewis, J. R. Lupski, D. W. Stockton, and B. A. Bejjani Of mice and men: tyrosinase modification of congenital glaucoma in mice but not in humans. Invest. Ophthalmol. Vis. Sci., April 1, 2006; 47(4): 1486 - 1490. [Abstract] [Full Text] [PDF]
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S. Chakrabarti, K. Kaur, I. Kaur, A. K. Mandal, R. S. Parikh, R. Thomas, and P. P. Majumder Globally, CYP1B1 Mutations in Primary Congenital Glaucoma Are Strongly Structured by Geographic and Haplotype Backgrounds Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 43 - 47. [Abstract] [Full Text] [PDF]
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S. W. M. John Mechanistic Insights into Glaucoma Provided by Experimental Genetics The Cogan Lecture Invest. Ophthalmol. Vis. Sci., August 1, 2005; 46(8): 2650 - 2661. [Full Text] [PDF]
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C. E. Willoughby, L. L. Y. Chan, S. Herd, G. Billingsley, N. Noordeh, A. V. Levin, Y. Buys, G. Trope, M. Sarfarazi, and E. Heon Defining the Pathogenicity of Optineurin in Juvenile Open-Angle Glaucoma Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3122 - 3130. [Abstract] [Full Text] [PDF]
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S. G. Panicker, A. K. Mandal, A. B. M. Reddy, V. K. Gothwal, and S. E. Hasnain Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma Invest. Ophthalmol. Vis. Sci., April 1, 2004; 45(4): 1149 - 1156. [Abstract] [Full Text] [PDF]
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D F Sena, S Finzi, K Rodgers, E Del Bono, J L Haines, and J L Wiggs Founder mutations of CYP1B1 gene in patients with congenital glaucoma from the United States and Brazil J. Med. Genet., January 1, 2004; 41(1): e6 - 6. [Full Text] [PDF]
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A. B. M. Reddy, S. G. Panicker, A. K. Mandal, S. E. Hasnain, and D. Balasubramanian Identification of R368H as a Predominant CYP1B1 Allele Causing Primary Congenital Glaucoma in Indian Patients Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4200 - 4203. [Abstract] [Full Text] [PDF]
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R Sitorus, S M Ardjo, B Lorenz, and M Preising CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients J. Med. Genet., January 1, 2003; 40(1): e9 - 9. [Full Text] [PDF]
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I. R. Stoilov, V. P. Costa, J. P. C. Vasconcellos, M. B. Melo, A. J. Betinjane, J. C. E. Carani, E. V. Oltrogge, and M. Sarfarazi Molecular Genetics of Primary Congenital Glaucoma in Brazil Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1820 - 1827. [Abstract] [Full Text] [PDF]
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D. B. Gould and S. W. M. John Anterior segment dysgenesis and the developmental glaucomas are complex traits Hum. Mol. Genet., May 15, 2002; 11(10): 1185 - 1193. [Abstract] [Full Text] [PDF]
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S. G. Panicker, A. B. M. Reddy, A. K. Mandal, N. Ahmed, H. A. Nagarajaram, S. E. Hasnain, and D. Balasubramanian Identification of Novel Mutations Causing Familial Primary Congenital Glaucoma in Indian Pedigrees Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1358 - 1366. [Abstract] [Full Text] [PDF]
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E. Aklillu, M. Oscarson, M. Hidestrand, B. Leidvik, C. Otter, and M. Ingelman-Sundberg Functional Analysis of Six Different Polymorphic CYP1B1 Enzyme Variants Found in an Ethiopian Population Mol. Pharmacol., March 1, 2002; 61(3): 586 - 594. [Abstract] [Full Text] [PDF]
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Y. Mashima, Y. Suzuki, Y. Sergeev, Y. Ohtake, T. Tanino, I. Kimura, H. Miyata, M. Aihara, H. Tanihara, M. Inatani, et al. Novel Cytochrome P4501B1 (CYP1B1) Gene Mutations in Japanese Patients with Primary Congenital Glaucoma Invest. Ophthalmol. Vis. Sci., September 1, 2001; 42(10): 2211 - 2216. [Abstract] [Full Text] [PDF]
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Y. Ko, J. Abel, V. Harth, P. Brode, C. Antony, S. Donat, H.-P. Fischer, M. E. Ortiz-Pallardo, R. Thier, A. Sachinidis, et al. Association of CYP1B1 Codon 432 Mutant Allele in Head and Neck Squamous Cell Cancer Is Reflected by Somatic Mutations of p53 in Tumor Tissue Cancer Res., June 1, 2001; 61(11): 4398 - 4404. [Abstract] [Full Text] [PDF]
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A. Vincent, G. Billingsley, M. Priston, D. Williams-Lyn, J. Sutherland, T. Glaser, E. Oliver, M. A Walter, G. Heathcote, A. Levin, et al. Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly J. Med. Genet., May 1, 2001; 38(5): 324 - 326. [Full Text]
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