Alternative titles; symbols
HGNC Approved Gene Symbol: CYP1B1
Cytogenetic location: 2p22.2 Genomic coordinates (GRCh38) : 2:38,067,509-38,076,151 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.2 | Anterior segment dysgenesis 6, multiple subtypes | 617315 | Autosomal recessive | 3 |
| Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset | 231300 | Autosomal recessive | 3 |
Sutter et al. (1994) reported the isolation and initial characterization of complete 5.1-kb cDNA corresponding to a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-responsive cDNA clone from a human keratinocyte cell line. The predicted 543-amino acid CYP1B1 protein was identified as a new gene subfamily of cytochrome P450, P4501B1 (CYP1B1). Southern blot analysis of genomic DNA indicated that the human CYP1B subfamily is likely to contain only this single gene. Northern blot analysis of RNA isolated from primary cultures of normal human epidermal keratinocytes showed approximately 100-fold increased levels of the CYP1B1 mRNA after 24-hour treatment with TCDD. Low levels of constitutive CYP1B1 mRNA were detected in 15 different human tissue samples. The results of Sutter et al. (1994) indicated that CYP1B1 is expressed in many normal human tissues.
Tang et al. (1996) determined that human CYP1B1 differs from its 2 most closely related members of the cytochrome P450 superfamily, CYP1A1 (108330) and CYP1A2 (124060), in the number of exons (3 vs 7) and chromosomal location (chromosome 2 vs chromosome 15). A single transcription initiation site was identified. Based on nucleotide sequence analysis, the CYP1B1 gene lacks a consensus TATA box in the promoter region and contains 9 TCDD-responsive enhancer core binding motifs located within a 2.5-kb pair of genomic fragments 5-prime-ward of the transcription start site.
Tang et al. (1996) determined that the CYP1B1 gene contains 3 exons. The putative ORF started in the second exon and was 1,629 bp long.
From a determination of the intron/exon junctions of the CYP1B1 gene, Stoilov et al. (1997) determined that it contains 3 exons and 2 introns. The entire coding sequence of the genes is contained in exons 2 and 3. This genomic structure agreed with that reported by Tang et al. (1996).
By analysis of 2 human/rodent somatic cell hybrid panels, Sutter et al. (1994) mapped the CYP1B1 gene to chromosome 2. Tang et al. (1996) refined the mapping of the CYP1B1 gene to chromosome 2p22-p21 by fluorescence in situ hybridization.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), or dioxin, is a prototype for a large class of halogenated aromatic hydrocarbons that are both widespread and persistent chemical pollutants. Sutter et al. (1994) noted that dioxin produces a broad spectrum of toxic responses and is a potent carcinogen and tumor-promoting agent in rodents. In humans, the skin appears to be the most common target organ, and the abnormalities are collectively termed chloracne. Chloracne is characterized by the formation of follicular keratinaceous cysts that may be accompanied by thickening and hyperkeratinization of the interfollicular epidermis. The biologic effects of dioxin are mediated through its high affinity and saturable binding to the dioxin receptor (126110). This receptor is a member of a distinct class of helix-loop-helix transcription factors. As characterized for cytochrome P450A1 (CYP1A1), activation of transcription of dioxin-inducible genes occurs through the binding of the ligand-occupied dioxin receptor to specific DNA recognition sequences within a dioxin-responsive enhancer, found upstream of the mRNA initiation site. Sutter et al. (1994) noted that CYP1B1 belongs to the multigene cytochrome P450 superfamily of monomeric mixed-function monooxygenases, responsible for the phase 1 metabolism of a wide range of structurally diverse substrates by inserting 1 atom of atmospheric oxygen into the substrate molecule, thereby creating a new functional group (e.g., -OH, -NH2, -COOH).
Rentas et al. (2016) found that expression of the RNA-binding protein MSI2 (607897) was upregulated in primitive human cord blood hematopoietic stem cells (HSCs) and was downregulated with HSC differentiation. Overexpression of MSI2 in HSCs significantly promoted self-renewal phenotypes, whereas knockdown of MSI2 reduced HSC self-renewal. Global analysis of MSI2-mRNA interactions revealed that MSI2 repressed expression of the transcription factor aryl hydrocarbon receptor (AHR; 600253) and AHR targets, particularly CYP1B1, which promotes HSC differentiation. Pharmacologic inhibition of CYP1B1 phenocopied the effect of MSI2 in promoting cord blood HSC self-renewal, and agonist-induced restoration of AHR activity reduced the effect of MSI2 overexpression on self-renewal. Cross-linking immunoprecipitation of MSI2 protein-RNA interactions, followed by sequencing and motif analysis, identified a consensus pentamer, (U/G)UAGU, within MSI2-binding sites. This motif was found in all regions of MSI2 target mRNAs, including coding regions, but predominantly mapped to 3-prime UTRs. Reporter gene assays and mutation analysis using the 3-prime UTRs of 2 putative MSI2 targets, CYP1B1 and HSP90 (HSP90AA1; 140571), which is also an AHR pathway component, confirmed that MSI2 directly downregulated translation of target mRNAs via the UAG motif. Rentas et al. (2016) concluded that MSI2 promotion of HSC self-renewal capacity is mainly due to inhibition of the AHR-CYP1B1 pathway.
Primary Congenital Glaucoma and Juvenile- or Adult-Onset Primary Open Angle Glaucoma
In a study of candidate genes identified in the critical region of chromosome 2p21 where a major gene for primary congenital glaucoma (GLC3A; 231300) had been mapped by linkage studies, followed by screening for coding sequence changes in the CYP1B1 gene, Stoilov et al. (1997) identified 3 different truncating mutations: a 13-bp deletion found in 1 consanguineous and 1 nonconsanguineous family (601771.0001); a single cytosine insertion observed in another 2 consanguineous families (601771.0002); and a large deletion found in an additional consanguineous family. In addition, a G-to-C transversion at nucleotide 1640 of the CYP1B1 coding sequence was found that caused a val432-to-leu amino acid substitution. This change created an EcoR57 restriction site, thus providing a rapid screening method. Heterozygosity for the val432-to-leu change was found in 51.4% of 70 normal individuals. This amino acid change was not in that part of CYP1B1 that represented conserved sequences, and both valine and leucine are neutral and hydrophobic. Their very similar aliphatic side groups differ by a single -CH2 group. Therefore, this change appeared to represent a common amino acid polymorphism that is not related to the primary congenital glaucoma phenotype.
Identification of CYP1B1 as the gene affected in primary congenital glaucoma was said by Stoilov et al. (1997) to be the first example in which mutations in a member of the cytochrome P450 superfamily results in a primary developmental defect. The finding was not unexpected, however, as a link between members of this superfamily and the processes of growth and differentiation had been postulated previously. They speculated that CYP1B1 participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development. Stoilov et al. (1997) demonstrated that a stable protein product is produced in the affected subjects of these families, and that the 3 mutations they described would be expected to result in a product lacking between 189 and 254 amino acids from the C terminus. This segment harbors the invariant cysteine of all known cytochrome P450 amino sequences; in CYP1B1 it is cys470. Schwartzman et al. (1987) implicated a cytochrome-P450-dependent arachidonate metabolite that inhibits Na+,K+-ATPase in the cornea in regulating corneal transparency and aqueous humor secretion. This finding is consistent with the clouding of the cornea and increased intraocular pressure, the 2 major diagnostic criteria for primary congenital glaucoma.
Stoilov et al. (1998) presented a comprehensive sequence analysis of the translated regions of the CYP1B1 gene in 22 primary congenital glaucoma (PCG) families and 100 randomly selected normal individuals. They identified 16 mutations (see, e.g., 601771.0003-601771.0005) and 6 polymorphisms, illustrating extensive allelic heterogeneity. The positions affected by these changes were evaluated by building a 3-dimensional homology model of the conserved C-terminal half of CYP1B1. These mutations may interfere with heme incorporation by affecting the hinge region and/or the conserved core structures (CCS) that determine the proper folding and heme-binding ability of P450 molecules. In contrast, all polymorphic sites were poorly conserved and located outside the CCS. Northern hybridization analysis showed strong expression of CYP1B1 in the anterior uveal tract, which is involved in secretion of the aqueous humor and in regulation of outflow facility, processes that could contribute to the elevated intraocular pressure characteristic of PCG. The 22 PCG families were from Turkey, the United States, Canada, and the United Kingdom. Onset of an aggressive form of glaucoma occurred at age 0 to 3 years.
In 25 Saudi families with primary congenital glaucoma mapping to chromosome 2p21, Bejjani et al. (1998) sequenced the coding exons of CYP1B1 and identified homozygosity or compound heterozygosity for 3 missense mutations (G61E, 601771.0003; R469W, 601771.0006; and D374N, 601771.0007) that segregated with the phenotype in 24 families. Additional clinical and molecular data on some mildly affected relatives showed variable expressivity of PCG in this population. Thus, genetic and environmental events must modify the effects of CYP1B1 mutations in ocular development. The small number of PCG mutations identified in this Saudi population made both neonatal and population screening attractive public health measures.
Following up on their report of 3 distinct CYP1B1 mutations in 24 Saudi families segregating PCG, Bejjani et al. (2000) analyzed 37 additional families and confirmed the initial finding of incomplete penetrance. Mutations and intragenic single-nucleotide polymorphisms (SNPs) were also analyzed by direct sequencing of all CYP1B1 coding exons. Eight distinct mutations were identified; the most common Saudi mutations, G61E, R469W, and D374N, accounted for 72%, 12%, and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (2 deletions and 3 missense mutations) were detected, each in a single family. Affected individuals from 5 families had no CYP1B1 coding mutations, and each family had a unique SNP profile. The identification of 8 distinct mutations in a single gene, on 4 distinct haplotypes, suggested a relatively recent occurrence of multiple mutations in CYP1B1 in Saudi Arabia. In 22 families, 40 apparently unaffected individuals had mutations and haplotypes identical to their affected sibs. Of these, 2 were subsequently diagnosed with glaucoma and 2 others had abnormal ocular findings consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggested the presence of a dominant modifier locus that is not linked genetically to CYP1B1. Linkage and Southern analyses excluded 3 candidate modifier loci, arylhydrocarbon receptor (AHR; 600253) on 7p15, the arylhydrocarbon receptor nuclear translocator (ARNT; 126110) on 1q21, and the CYP2D6 gene (124030) on 22q13.1.
Vincent et al. (2002) stated that 'early-onset glaucoma' refers to genetically heterogeneous conditions for which glaucoma manifests at age 5 to 40 years and for which only a small subset had been molecularly characterized. They studied the role of the MYOC, CYP1B1, and PITX2 (601542) genes in 60 patients with juvenile or early-onset glaucoma. By a combination of SSCP and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) and CYP1B1 mutations in 3 (5%); no PITX2 mutations were detected. The range of phenotypic expression associated with MYOC and CYP1B1 mutations was greater than expected. MYOC mutations included cases of juvenile glaucoma with or without pigmentary glaucoma and mixed-mechanism glaucoma. CYP1B1 mutations involved cases of juvenile open angle glaucoma as well as cases of congenital glaucoma. The study of a Canadian family with autosomal dominant glaucoma showed the segregation of both MYOC (601652.0013) and CYP1B1 (601771.0012) mutations with disease; however, in this family, the mean age at onset of carriers of the MYOC mutation alone was 51 years, whereas carriers of both the MYOC and CYP1B1 mutations had an average age at onset of 27 years. This work emphasized the genetic heterogeneity of juvenile glaucoma, and suggested that it and congenital glaucoma are allelic variants and that the spectrum of expression of MYOC and CYP1B1 mutations is greater than expected. It also appeared that CYP1B1 may act as a modifier of MYOC expression and that these 2 genes may interact through a common pathway.
Ming and Muenke (2002) stated that mutations in CYP1B1 are present in a substantial proportion of patients with congenital glaucoma. Both CYP1B1 and the MYOC gene (601652) are expressed in the iris, trabecular meshwork, and ciliary body of the eye.
Mutation in the CYP1B1 gene is a major cause of primary congenital glaucoma (PCG). Mutation in the CYP1B1 gene has also been associated with cases of juvenile-onset glaucoma in some families in which other members have PCG, suggesting that shared or overlapping mechanisms may predispose to both forms of glaucoma. In 2 families, Melki et al. (2004) described the occurrence of PCG and POAG in members of a single sibship, all of whom were compound heterozygous for mutations in the CYP1B1 gene (601771.0013-601771.0016). Neither family had a mutation of the MYOC gene. To investigate the role of CYP1B1 mutations in POAG predisposition, irrespective of the presence of an MYOC mutation, Melki et al. (2004) studied CYP1B1 coding region variation in 236 unrelated French Caucasian POAG patients. They found 11 (4.6%) who carried a mutation of the CYP1B1 gene (see 601771.0017) and no MYOC mutation. The patients showed juvenile or middle-age onset of disease with a median age at diagnosis of 40 years (range, 13 to 52 years), significantly earlier than in noncarrier patients. Apart from 1, all mutations detected in POAG patients were previously associated with PCG. Melki et al. (2004) concluded that mutation in the CYP1B1 gene represents a significant risk for early-onset POAG and may also modify the glaucoma phenotype in patients who do not carry an MYOC mutation.
Chavarria-Soley et al. (2008) performed functional characterization of 4 common CYP1B1 haplotypes (RAVDN, GSLDN, RALDS, and RALDN) consisting of 5 frequent nonsynonymous SNPs (rs10012, rs1056827, rs1056836, rs1056837, and rs1800440). There was significant variation in molar enzymatic activity (U/mol), with the most active haplotype RAVDN showing 4 times more activity than the least active haplotype GSLDN. The microsomal CYP1B1 abundance (mol/mg total protein) showed highest levels in GSLDN and lowest levels in RALDS. Relative CYP1B1 activity (U/mg total protein) was lowest in RALDS and highest in RAVDN. The authors also analyzed 5 CYP1B1 mutations that had been reported in PCG patients: G61E, N203S, L343del, Y81N (601771.0017), and E229K. The G61E, N203S, and L343del mutations had molar enzymatic activity that was less than 10% of that of their respective background haplotype, and there was a significant reduction in microsomal CYP1B1 abundance with the L343del, Y81N, and E229K variants compared to background haplotype. Chavarria-Soley et al. (2008) classified Y81N and E229K as hypomorphic alleles rather than mutations because their relative activity values were intermediate between bona fide mutations and the common haplotype with the lowest activity. The authors proposed that CYP1B1 mutations can act either by reducing enzymatic activity (G61E and N203S), reducing the abundance of the enzyme (Y81N and E229K), or both (L343del), and that mutations that cause a 10-fold or greater reduction in relative activity result in PCG.
In a Spanish patient with primary congenital glaucoma, Lopez-Garrido et al. (2009) identified homozygosity for a missense mutation (601771.0018) in the CYP1B1 gene, which was carried in heterozygous state in her unaffected father but not her mother. Segregation analysis of markers on chromosome 2 was consistent with paternal uniparental isodisomy. Lopez-Garrido et al. (2009) stated that this was the first reported case of uniparental isodisomy resulting in primary congenital glaucoma, and the fifth reported case of paternal uniparental isodisomy for chromosome 2. In addition, the authors noted that the absence of a clinical phenotype other than glaucoma supported previous observations regarding the lack of paternally imprinted genes on chromosome 2 with major phenotypic effects.
Anterior Segment Dysgenesis 6
Vincent et al. (2001) reported compound heterozygosity for a missense mutation (601771.0009) and a nonsense mutation (601771.0010) in the CYP1B1 gene in a male of Native Indian (Mohawk)/French Canadian background with anterior segment dysgenesis-6 (ASGD6; 617315), which included Peters anomaly with secondary congenital glaucoma.
In 11 patients with Peters anomaly from 10 Saudi Arabian families, Edward et al. (2004) analyzed 5 anterior segment dysgenesis (ASGD)-associated genes, and identified homozygosity for mutations in the CYP1B1 gene in 6 patients from 5 families. Five of those patients, including a brother and sister from a previously reported PCG pedigree (Bejjani et al., 1998), were homozygous for the G61E variant (601771.0003) that had been previously reported in PCG patients. The remaining patient with Peters anomaly, who was homozygous for a 10-bp deletion (601771.0020), also belonged to a previously reported PCG pedigree (Bejjani et al., 2000). Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations.
In a 2-week-old Mexican boy with an ASGD phenotype of internal corneal ulcer of von Hippel, Oliva-Bienzobas et al. (2017) identified homozygosity for a 1-bp deletion in the CYP1B1 gene (601771.0021). The deletion was present in heterozygosity in his consanguineous parents, and was not found in public variant databases.
Thanikachalam et al. (2020) performed exome sequencing in 24 families from south Florida with various types of anterior segment dysgenesis, and identified homozygosity for a 1-bp deletion in the CYP1B1 gene (601771.0011) in a 13-year-old Hispanic boy with bilateral Peters anomaly. The authors noted that the same mutation had previously been identified in patients with primary congenital glaucoma by Belmouden et al. (2002).
Possible Association with Breast Cancer
Activation of 17-beta-estradiol (E2) through the formation of catechol estrogen metabolites and the C-16-alpha hydroxylation product has been postulated to be a factor in mammary carcinogenesis. CYP1B1 exceeds other P450 enzymes in both estrogen hydroxylation activity and expression level in breast tissue. To determine whether inherited variants of CYP1B1 differ from wildtype CYP1B1 in estrogen hydroxylase activity, Hanna et al. (2000) expressed recombinant wildtype and 5 polymorphic variants. They found that the activity of variant enzymes exceeded that of wildtype CYP1B1. The authors suggested that interindividual differences in breast cancer risk associated with estrogen-mediated carcinogenicity may be related to these polymorphisms.
MicroRNAs are small noncoding RNAs that regulate gene expression through translational repression or mRNA cleavage. Tsuchiya et al. (2006) identified a recognition element for MIRN27B (610636) in the 3-prime UTR of CYP1B1. Database analysis indicated that this element is highly conserved between human, mouse, and rat. Immunohistochemical analysis of 24 breast cancer patients detected high CYP1B1 protein levels in cancer cells, and in most of these cases, a high level of CYP1B1 protein was accompanied by decreased expression of MIRN27B. Transfection of antisense MIRN27B decreased the level of endogenous MIRN27B in MCF7 breast cancer cells in a concentration- and time-dependent manner, and this was associated with increased CYP1B1 protein levels and enzymatic activity. Tsuchiya et al. (2006) concluded that the expression of CYP1B1 is posttranscriptionally regulated by MIRN27B.
Libby et al. (2003) generated mice deficient in CYP1B1 and found that they have ocular drainage structure abnormalities resembling those reported in human primary congenital glaucoma patients. Using Cyp1b1 -/- mice, Libby et al. (2003) identified the tyrosinase gene (TYR; 606933) as a modifier of the drainage structure phenotype, with tyrosinase deficiency increasing the magnitude of dysgenesis. The severe dysgenesis in eyes lacking both Cyp1b1 and Tyr was alleviated by administration of the tyrosinase product dihydroxyphenylalanine (L-DOPA). Tyr also modified the drainage structure dysgenesis in mice with a mutant Foxc1 gene (601090), which is also involved in primary congenital glaucoma. Libby et al. (2003) concluded that their studies raised the possibility that a tyrosinase/L-DOPA pathway modifies human primary congenital glaucoma.
In 1 consanguineous and 1 nonconsanguineous family, Stoilov et al. (1997) demonstrated that affected individuals with primary congenital glaucoma (buphthalmos) (GLC3A; 231300) were homozygous for a 13-bp deletion in the CYP1B1 gene. The deletion removed nucleotides 1410 to 1422 from exon 3 of the gene and resulted in a frameshift that truncated the open reading frame by creating a premature stop codon (TGA) 203 bp downstream of the deletion.
In 2 consanguineous families, Stoilov et al. (1997) identified a single cytosine insertion in homozygous state in the CYP1B1 gene in members with primary congenital glaucoma (GLC3A; 231300). The insertion was in a stretch of 6 cytosines normally located between nucleotide positions 1209 and 1214 in exon 2. The insertion created a frameshift with a premature stop codon (TGA) 106 bp downstream from the site of the insertion.
Glaucoma 3, Primary Congenital, A
In 17 of 24 Saudi Arabian families, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) was associated with homozygosity for a 3987G-A transition in exon 2 of the CYP1B1 gene, leading to a gly61-to-glu (G61E) amino acid substitution. In 3 other families, affected members were compound heterozygotes for this mutation and 2 other missense mutations in exon 3 (601771.0006 and 601771.0007, respectively).
In 4 separate Turkish families with primary congenital glaucoma (PCG), Stoilov et al. (1998) found that 5 PCG chromosomes carried a G-to-A transition at nucleotide 528, predicted to result in a G61E substitution at the hinge region of the CYP1B1 protein.
In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with PCG and identified 2 mutations in 11 (34%) patients: the G61E mutation and a 4339delG mutation (601771.0011). Two patients were homozygous for G61E and 7 others for 4339delG, whereas the remaining 2 were compound heterozygotes.
Anterior Segment Dysgenesis 6, Peters Anomaly Subtype
In 5 patients with Peters anomaly (ASGD6; 617315) from 4 consanguineous Saudi Arabian families, including a brother (PE-10) and sister (PE-11) from a previously reported PCG pedigree (KKECG-122; Bejjani et al., 1998), Edward et al. (2004) identified homozygosity for the G61E mutation in the CYP1B1 gene. Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations.
In 5 primary congenital glaucoma (GLC3A; 231300) families of U.S., British, or Turkish origin, Stoilov et al. (1998) found 5 chromosomes with a duplication of 10 nucleotides beginning at nucleotide 1546 and causing frameshift with premature termination and deletion of 140 amino acids.
In a U.S. family with primary congenital glaucoma (GLC3A; 231300) (family 1007), Stoilov et al. (1998) found that children with PCG were homozygous for a gly365-to-trp mutation and their mother was heterozygous for the mutation. The father, however, was found to be homozygous for the wildtype allele. No evidence for nonpaternity was found, suggesting that the father represented a case of germinal mosaicism.
In 3 Saudi Arabian families with primary congenital glaucoma (GLC3A; 231300), Bejjani et al. (1998) found homozygosity for an 8242C-T transition in exon 3 of the CYP1B1 gene, leading to an arg469-to-trp (R469W) amino acid substitution. In 1 other Saudi Arabian family, this mutation was present in compound heterozygous state with the G61E mutation in exon 2 (601771.0003).
In a Saudi Arabian family, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) associated with homozygosity for a 7957G-A transition in the CYP1B1 gene, leading to an asp374-to-asn (D374N) amino acid substitution. This same mutation in exon 3 was present in compound heterozygous state with the G61E mutation in 2 other families (601771.0003).
Plasilova et al. (1999) reported mutation screening of 43 patients from 26 Slovak Rom (Gypsy) families. The Slovak Rom population is known to have an unusually high frequency of primary congenital glaucoma (GLC3A; 231300). A homozygous G-to-A transition at nucleotide 1505 in a highly conserved region of exon 3 was detected in all families. This resulted in a lysine-to-glutamine substitution, affecting the conserved K helix region of the CYP1B1 molecule. This mutation appeared on a common haplotype in all patients. Plasilova et al. (1999) concluded that this mutation originated from a single ancestral mutational event.
Sivadorai et al. (2008) analyzed the CYP1B1 gene in 21 patients from 16 unrelated Bulgarian Gypsy families and detected 5 different mutations. The E387K mutation was detected in only 3 (8%) of 38 mutant alleles, and only 4 (0.56%) of 715 healthy Gypsy controls were heterozygous for the E387K mutation. Sivadorai et al. (2008) concluded that the molecular basis of primary congenital glaucoma in the Gypsy population is unresolved and that diagnostic analysis must extend beyond the E387K mutation.
In a Native American (Mohawk)/French Canadian male with Peters anomaly and secondary congenital glaucoma (ASGD6; 617315), Vincent et al. (2001) identified compound heterozygosity for a 3807T-C transition in the CYP1B1 gene, resulting in a met1-to-thr (M1T) substitution at the initiating codon, and a 3976G-A transition, resulting in a trp57-to-ter (W57X) substitution (601771.0010).
For discussion of the trp57-to-ter (W57X) mutation in the CYP1B1 gene that was found in compound heterozygous state in a patient with anterior segment dysgenesis-6 (ASGD6; 617315) by Vincent et al. (2001), see 601771.0009.
Glaucoma 3, Primary Congenital, A
In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with primary congenital glaucoma (GLC3A; 231300) and identified 2 mutations in the CYP1B1 gene in 11 (34%) patients: G61E (601771.0003), previously found in Turkish and Algerian patients, and a 4339G deletion (4339delG) that caused a frameshift at residue 179. Seven patients were homozygous for 4339delG and 2 others for G61E, whereas the remaining 2 were compound heterozygotes. Close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG. The occurrence of the mutation was tentatively estimated at between 900 and 1,700 years earlier.
Anterior Segment Dysgenesis 6, Peters Anomaly Subtype
In a 13-year-old Hispanic boy (14-II:1) with bilateral Peters anomaly (ASGD6; 617315), Thanikachalam et al. (2020) identified homozygosity for the c.535delG mutation (c.535delG, NM_000104.3) in the CYP1B1 gene, causing a frameshift predicted to result in a premature termination codon (Ala179ArgfsTer18). The authors noted that same mutation had previously been identified in patients with primary congenital glaucoma by Belmouden et al. (2002).
In a Canadian patient with early-onset glaucoma and a strong family history of autosomal dominant glaucoma with variable age at onset (GLC1A; 137750), Vincent et al. (2002) found a gly399-to-val mutation in the MYOC gene (G399V; 601652.0013) and a 7940G-A transition in exon 3 of the CYP1B1 gene, resulting in an arg368-to-his (R368H) mutation. All participants with glaucoma in this family carried the G399V mutation. Individuals carrying both the CYP1B1 and MYOC mutations had juvenile-onset open angle glaucoma with a mean age at onset of 27 years (range, 23 to 38 years). Individuals with only the MYOC mutation had a mean age at onset of 51 years (range, 48 to 64 years). The R368H mutation had previously been reported by Bejjani et al. (2000) in homozygosity in Saudi Arabian patients with congenital glaucoma (GLC3A; 231300) with incomplete penetrance and was not found in 100 Saudi Arabian control chromosomes. Vincent et al. (2002) identified the R368H mutation in 1 of 140 (0.7%) control subjects. The individual was of Saudi Arabian descent and had autosomal recessive retinitis pigmentosa but no glaucoma.
In 2 Roma/Gypsy probands with congenital glaucoma, Azmanov et al. (2011) identified heterozygosity for the R368H mutation in the CYP1B1 gene; 1 of the patients was also heterozygous for the Gypsy founder mutation R299X in the LTBP2 gene (602091.0001). The authors stated that the pathogenicity of R368H in these patients was uncertain.
Pasutto et al. (2010) detected marked reduction in enzymatic activity of CYP1B1 carrying the R368H mutation in in vitro functional assays.
Lek et al. (2016) noted a high allele frequency (0.0294) of this variant in the South Asian population in the ExAC database.
In 4 sisters from a French Caucasian family, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene: a gly232-to-arg (G232R) substitution and a glu387-to-lys substitution (E387K; 601771.0014). Two of the sisters had primary congenital glaucoma (GLC3A; 231300); the other 2 sisters had adult-onset (ages 35 and 40 years, respectively) primary open angle glaucoma (see 231300). No mutation in the MYOC gene (601652) was present.
For discussion of the glu387-to-lys (E387K) mutation in the CYP1B1 gene that was found in patients with either primary congenital glaucoma (GLC3A; 231300) or primary open angle glaucoma by Melki et al. (2004), see 601771.0013.
In 8 Roma/Gypsy probands with congenital glaucoma, Azmanov et al. (2011) identified homozygosity or compound heterozygosity for the E387K mutation in the CYP1B1 gene.
In a French Caucasian family ascertained through a proband who developed juvenile-onset primary open angle glaucoma (see 231300) at the age of 13 years, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene in the proband and in his brother: a 1-bp deletion (3979delA) and an asn423-to-tyr substitution (N423Y; 601771.0016). The proband's brother had primary congenital glaucoma (GLC3A; 231300). The mother carried the N423Y mutation but showed no glaucoma symptoms at the age of 49 years. The father could not be examined.
For discussion of the asn423-to-tyr (N423Y) mutation in the CYP1B1 gene that was found in compound heterozygous state in patients with either primary congenital glaucoma (GLC3A; 231300) or primary open angle glaucoma by Melki et al. (2004), see 601771.0015.
In 2 unrelated French Caucasian patients with adult-onset primary open angle glaucoma (see 231300), Melki et al. (2004) identified a heterozygous 4046T-A transversion in exon 2 of the CYP1B1 gene, resulting in a tyr81-to-asn (Y81N) substitution. One of the 2 patients, diagnosed with glaucoma at the age of 52 years, had 2 sons heterozygous for the Y81N mutation who had onset of primary open angle glaucoma at 39 and 44 years of age, respectively. No mutation in the MYOC gene (601652) was present.
Chavarria-Soley et al. (2008) analyzed 5 CYP1B1 mutations that had been reported in PCG patients: Y81N, G61E, N203S, L343del, E229K. The G61E, N203S, and L343del mutations had molar enzymatic activity that was less than 10% of that of their respective background haplotype, and there was a significant reduction in microsomal CYP1B1 abundance with the L343del, Y81N, and E229K variants compared to background haplotype. Chavarria-Soley et al. (2008) classified Y81N and E229K as hypomorphic alleles rather than mutations because their relative activity values were intermediate between bona fide mutations and the common haplotype with the lowest activity. The authors proposed that CYP1B1 mutations can act either by reducing enzymatic activity (G61E and N203S), reducing the abundance of the enzyme (Y81N and E229K), or both (L343del), and that mutations that cause a 10-fold or greater reduction in relative activity result in PCG.
In a Spanish female infant with primary congenital glaucoma (GLC3A; 231300), Lopez-Garrido et al. (2009) identified homozygosity for a 783C-A transversion in exon 2 of the CYP1B1 gene, resulting in a phe261-to-leu (F261L) substitution. Her unaffected father, brother, and paternal grandfather were heterozygous for the F261L mutation, which was not present in her mother, who instead carried a heterozygous G168D mutation in CYP1B1, as did another unaffected brother. Segregation analysis of markers on chromosome 2 were consistent with paternal uniparental isodisomy in the proband, which was not present in any other family members. Lopez-Garrido et al. (2009) noted that the F261L mutation had been found in a different branch of this family by Campos-Mollo et al. (2009) and that functional studies of catalytic activity had revealed F261L to be a null allele.
In a patient with juvenile-onset primary open angle glaucoma (see 231300) diagnosed at 6 years of age, Pasutto et al. (2010) detected a heterozygous C-to-T transition at nucleotide 155 of the CYP1B1 gene that resulted in a substitution of leucine for proline at codon 52 (P52L). No mutations in the MYOC (601652), optineurin (OPTN; 602432), or WD repeat domain 36 (WDR36; 609669) genes were present. In vitro functional assays demonstrated marked reduction in CYP1B1 enzymatic activity.
In a boy (PE-09) with Peters anomaly (ASGD6; 617315), from a previously reported Saudi Arabian pedigree (KKECG-106; Bejjani et al., 2000) with primary congenital glaucoma (GLC3A; 231300), Edward et al. (2004) identified homozygosity for a 10-bp deletion (c.4238del10), causing a frameshift predicted to result in a premature termination codon 2 residues downstream. Homozygosity for the deletion previously had been found in the proband's sister, who had PCG, as well as in another another clinically unaffected family member (Bejjani et al., 2000). Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations.
In a 2-week-old Mexican boy with anterior segment dysgenesis presenting as internal corneal ulcer of von Hippel (ASGD6; 617315), Oliva-Bienzobas et al. (2017) identified homozygosity for a 1-bp deletion (c.830delT, ENST00000610745.4) in the CYP1B1 gene, causing a frameshift predicted to result in an immediate stop codon (leu277-to-ter; L277X). The deletion was present in heterozygosity in his consanguineous parents, and was not found in the 1000 Genomes Project, NHLBI ESP, or ExAC databases.
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