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Novel CYP1B1 mutations and a possible prognostic use for surgical management of congenital glaucoma.

ABSTRACT: AIM:To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor for success rates in the surgical management of Egyptian congenital glaucoma patients. METHODS:Totally 42 eyes of 29 primary congenital glaucoma patients were operated on with combined trabeculotomy/trabeculectomy with mitomycin-C and followed up at 1d, 1wk, 1, 6 and 12mo postoperatively. Genomic DNA was extracted from peripheral blood leukocytes. Coding regions of CYP1B1 gene were amplified using 13 pairs of primers, screened for mutations using single-strand conformation polymorphism followed by sequencing of both strands. Efficacy of the operation was graded as either a success [maintaining intraocular pressure (IOP) less than 21 mm Hg with or without anti-glaucoma medication], or a failure (IOP more than 21 mm Hg with topical antiglaucoma medications). RESULTS:Seven novel mutations out of a total of 15 different mutations were found in the CYP1B1 genes of 14 patients (48.2%). The presence of CYP1B1 gene mutations did not correlate with the failure of the surgery (P=0.156, odds ratio=3.611, 95%CI, 0.56 to 22.89); while the positive consanguinity strongly correlated with failure of the initial procedure (P=0.016, odds ratio=11.25, 95%CI, 1.57 to 80.30). However, the Kaplan-Meier survival analysis revealed a significantly lower time of IOP control in the subgroup with mutations in CYP1B1 versus the congenital primary glaucoma group without mutations (log rank test, P=0.015). CONCLUSION:Seven new CYP1B1 mutations are identified in Egyptian patients. Patients harboring confirmed mutations suffered from early failure of the initial surgery. CYP1B1 mutations could be considered as a prognostic factor for surgery in primary congenital glaucoma.

SUBMITTER: Khafagy MM

PROVIDER: S-EPMC6469545 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Novel CYP1B1 mutations and a possible prognostic use for surgical management of congenital glaucoma.

Khafagy Mohamed M MM El-Guendy Nadia N Tantawy Marwa A MA Eldaly Mohamed A MA Elhilali Hala M HM Abdel Wahab Abdel Hady A AHA

International journal of ophthalmology 20190418 4

<h4>Aim</h4>To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor for success rates in the surgical management of Egyptian congenital glaucoma patients.<h4>Methods</h4>Totally 42 eyes of 29 primary congenital glaucoma patients were operated on with combined trabeculotomy/trabeculectomy with mitomycin-C and followed up at 1d, 1wk, 1, 6 and 12mo postoperatively. Genomic DNA was extracted from peripheral blood leukocytes. Coding regions of CYP1B1 gene were amplif ...[more]

PMID: 31024815

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Project description:Primary congenital glaucoma (PCG) is the most common type of infantile glaucoma, yet it remains a relatively rare disease, because the disease is often transmitted in an autosomal recessive pattern. However, PCG occurs up to 10 times more frequently in certain ethnic and geographical groups where consanguineous relationships are common. The aim of this study was to investigate the distribution of mutations in the cytochrome P450 1B1 gene ( CYP1B1 ) in patients with PCG among different populations around the world from 2011 until May 2016. We referred to the electronic databases, such as Medline, Clinicalkey, Scopus, and ScienceDirect, to search for articles that were published in this area. Nineteen records were included in this qualitative synthesis. CYP1B1 mutations were assessed in 1,220 patients with PCG and identified in 41.6% of them. According to these studies, 99 mutations including 60 novel mutations were found. Nonsignificant difference in the sex ratio has been reported. This current review shows that consanguinity plays an important role in the PCG pathogenesis and transmission; however, sporadic mutations have been found in some cases. A difference in penetrance was highlighted by some mutations. The CYP1B1 mutations were mostly found in the Middle East and the Maghreb with a rate of 64.8 and 54.4%, respectively, followed by Europe (34.7%), Asia (21.3%), and finally the United States (14.9%). Founder mutations in different geographical areas have been discovered. For instance, the p.Gly61Glu, p.Arg390His, p.Gly61Glu, c.4,339delG, p.E387Lys, and p.Val320Leu were considered founder mutations for Iran/Saudi Arabia, Pakistan, Lebanon, Morocco, Europe, and Vietnam/South Korea, respectively. Many common mutations in different countries were found, such as in Morocco, where its mutations were similar to seven other countries. These findings suggest that the ethnic differences and the geographical distribution of PCG give us a large CYP1B1 mutation pattern. Genetic tests looking for founder and common mutations should be the first step in genetic screening for patients with PCG.

Project description:BACKGROUND: CYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG). This study was undertaken to identify mutations in CYP1B1 in the Western region of Saudi Arabia. METHODS: Blood of patients who had typical findings of PCG, were screened by direct sequencing of all coding exons and splice junctions of the CYP1B1 gene. RESULTS: 34 patients were studied; 18 patients belonged to 8 families, and 16 patients were non-familial, isolated PCG. Consanguinity was found in 27/34 (79.4%) of cases. All patients were diagnosed to have bilateral PCG at birth except one child, who had glaucoma in the right eye. More males (61.8%) were affected than females (38.2%). 79.4% (27/34) of patients were solved with pathogenic mutations and 20.6% (7/34) remained unsolved. Of the solved ones, 22.2% (6/27) of patients carry a pathogenic allele on one allele while the other allele remained yet to be determined. Direct sequencing of exon 2 revealed two pathogenic variants (p.Gly61Glu, p.Glu229Lys). P.Gly61Glu substitution was found both homozygously in 63% (17/27) of cases, and heterozygously in one patient. P.Glu229Lys variant was found heterozygous in 3.7% (1/27) of cases. One pathogenic variant (p.Arg469Trp) was found in exon 3, and is present homozygously in 14.8% (4/27) of cases while four patients have this variant heterozygously. All mutations were reported previously in the Saudi population, except p.Glu229Lys. Severe cases were associated with p.Gly61Glu, and p.Arg469Trp in 50% and 30% of ten patients respectively. CONCLUSIONS: This study confirms that CYP1B1 mutations are the most frequent cause of PCG in the Saudi population, with p.Gly61Glu being the major disease-associated mutation. P.Glu229Lys is a newly discovered mutation in our PCG patients. Patient lacking mutation in CYP1B1 gene seems likely, to have another genetic loci involved in the pathogenesis of the disease, and need further study. Genetic studies of recessive diseases such as PCG is important in consanguineous populations, since it will increase awareness and allows genetic counseling to be offered to patients and their relatives. This will not only reduce the disease to be inherited to future generations, but will also reduce the disease burden in the community.

Project description:PURPOSE: To analyze the contributions of cytochrome P4501B1 (CYP1B1) mutations to primary congenital glaucoma (PCG) in Spanish patients. METHODS: We analyzed, by polymerase chain reaction (PCR) DNA sequencing, the presence of promoter (-1 to -867) and exon CYP1B1 mutations in 38 unrelated Spanish probands affected by PCG. Functional analysis of nine identified mutations was performed measuring ethoxyresorufin O-deethylation activity and CYP1B1 stability in transiently transfected human embryonic kidney 293T (HEK-293-T) cells. RESULTS: We found a total of 16 different mutations in 13 (34.2%) index cases. The identified mutations included nine missense and three nonsense nucleotide changes, three small deletions, and a short duplication. Eleven probands were compound heterozygotes and two were heterozygotes. Six of the identified mutations were novel (A106D, E173X, F261L, E262X, W341X, and P513_K514del). Mutations T404fsX30 and R355fsX69 were the most prevalent among index cases and were detected in six (23.0%) and three (11.5%) patients, respectively. Functional analysis showed that the three nonsense mutants assayed (E173X, E262X, and W341X) and F261L were null alleles. Of the remaining mutants, four (P52L, G61E, Y81N, and E229K) showed catalytic activities ranging from 20% to 40% of wild-type CYP1B1 and high protein instability. Mutation P400S showed normal catalytic activity and moderate instability. These five mutants were classified as hypomorphic alleles. Patients carrying two null alleles showed severe phenotypes featured by very early PCG onset usually at birth or in the first month of life (0.6+/-0.9 months). Incomplete penetrance was detected in patients carrying hypomorphic alleles. CONCLUSIONS: Our data indicate that approximately one-third of Spanish patients with PCG carry loss-of-function CYP1B1 and show that null alleles are associated with the most severe phenotypes. Hypomorphic alleles may contribute to some cases of incomplete penetrance.

Project description:Primary congenital glaucoma (PСG) is a visual organ pathology that leads to progressive blindness and poor vision in children. Its main cause is an anomaly of the anterior chamber angle. Most cases of PСG are sporadic, but familial cases with an autosomal recessive (predominantly) and autosomal dominant (rare) type of inheritance have been described. Congenital glaucoma is a rare condition (1 case per 10,000-20,000 newborns), but its prevalence is substantially higher (up to 1 case per 250 newborns) in countries where consanguineous marriages are common. Mutations in the CYP1B1 gene, which encodes cytochrome P450 1B1, are the most common cause of autosomal recessive primary congenital glaucoma. This enzyme is known to be involved in retinoic acid metabolism and is necessary for normal eye development. The aim of this work was to assess the polymorphism of the CYP1B1 gene among West Siberian patients with primary congenital glaucoma. Direct automatic Sanger sequencing of exons and adjacent splicing sites of the CYP1B1 gene was carried out in 28 people with the PCG phenotype from a West Siberian region. As a result, in the sample of the white population we examined, pathogenic variants previously described in other ethnic groups were revealed: E387K (rs55989760), R444* (rs377049098), R444Q (rs72549376), and P437L (rs56175199), as well as novel single-nucleotide deletion p.F114Lfs*38 in the CYP1B1 gene. The latter can cause a frame shift, changed amino acid composition, and a formation of truncated in the protein. None of the detected mutations were found in the control sample of ophthalmologically examined individuals without PCG (100 people). Variants R444* (rs377049098) and R444Q (rs72549376) were not found in the general population sample either (576 randomly selected West Siberia residents). All the detected mutations caused the development of the autosomal recessive form of primary congenital glaucoma. The most severe clinical phenotype was observed in carriers of mutations in codon 444 of the gene. Consequently, in children with signs of increased intraocular pressure, molecular genetic analysis of the CYP1B1 gene is advisable for early diagnosis and timely initiation of PCG therapy.

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Novel CYP1B1 mutations and a possible prognostic use for surgical management of congenital glaucoma.

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Novel CYP1B1 mutations and a possible prognostic use for surgical management of congenital glaucoma.

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