A Novel CYP1B1 Mutation with Congenital Glaucoma and Total Aniridia

Alzuhairy, Sultan; Abu-Amero, Khaled K; Al-Shahwan, Sami; Edward, Deepak P.

doi:10.3109/13816810.2013.833635

Cited by 10 publications

(5 citation statements)

References 2 publications

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“…The conclusion is that the iris malformations in these patients may be due to mutation in another gene that has a role in the formation of the eye, and thus aniridia is phenotypically present (9). This has been supported by results of the study which showed that mutations in the CYP1B1 gene can lead to the appearance of congenital aniridia and glaucoma (10).…”

Section: Discussionsupporting

confidence: 75%

PAX6 gene analysis in Serbian patients with aniridia

Cvetković¹,

Ćuk²

2016

Medicinski podmladak

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SažetakUvod: Aniridija je retka kongenitalna anomalija oka, praćena različitim oftalmološkim tegobama. Uzroci ovog oboljenja su mutacije u PAX6 genu (engl. paired box 6, gen sa blokom koji kodira parni domen) ili delecija lokusa na kratkom kraku jedanaestog hromozoma koja može da bude parcijalna ili kompletna. U ovoj studiji je ispitivana sekvenca PAX6 gena kod četiri nesrodna bolesnika sa aniridijom.Cilj: Ispitavanje celokupne kodirajuće sekvence PAX6 gena kod naših bolesnika u cilju otkrivanja mutacija u ovom genu.Materijal i metode: Iz uzoraka periferne krvi izolovana je DNK bolesnika. Nakon toga je metodom polimerazne lanča-ne reakcije (PCR metodom) izvršena amplifikacija kodirajućih PAX6 egzona i graničnih regiona i dati uzorci su direktno sekvencirani metodom po Sangeru.Rezultat: Kod jednog bolesnika je nađena mutacija po tipu insercije (c.342-2insC) u drugom intronu PAX6 gena. Kod preostala tri bolesnika nije nađeno odstupanje u sekvenci PAX6 gena.Zaključak: Ovo su prvi rezultati analize PAX6 gena u Srbiji. Osim najčešćih mutacija, delecija različitog obima u kodirajućem regionu ovog gena, mogući uzroci aniridije su i druge vrste mutacija. Insercija pronađena u ovoj studiji nije prijavljena ranije. Moguće je i da su mutacije u drugim genima povezane sa malformacijama dužice, što može da objasni nalaz normalne sekvence kod tri bolesnika sa aniridijom.Ključne reči: aniridija, PAX6 gen, kongenitalne anomalije oka Abstract Introduction: Aniridia is a rare congenital eye anomaly associated with various ophthalmological problems. Some of the causes of this disease are mutations in the PAX6 gene or deletion of loci on the short arm of chromosome eleven, which can be complete or partial. In this study, PAX6 gene sequence was analysed in four unrelated patients.Aim: Examination of the entire coding sequence of the PAX6 gene in our patients in order to detect mutations in this gene.Material and Methods: Patients' DNA was isolated from samples of peripheral blood. All exons and flanking intronic sequences of the PAX6 gene were amplified using PCR and screened for mutation with direct DNA sequencing by Sanger method.Results: In one patient, the insertion type of mutation (c.342-2insC) was found in the second intron of the PAX6 gene. Other three patients had normal PAX6 sequence although they had phonotypical expression of aniridia.Conclusion: These are first results of PAX6 gene analysis in Serbia. Apart from most common mutations, deletions of various extent in coding regions of PAX6 gene, other types of mutations are also possible causes of aniridia. The insertion found in this study has not been reported before. It is also possible that mutations in other genes are associated with iris malformation, which can explain the finding of normal PAX6 gene sequence in three patients with aniridia.

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Section: Discussionsupporting

confidence: 75%

PAX6 gene analysis in Serbian patients with aniridia

Cvetković¹,

Ćuk²

2016

Medicinski podmladak

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“…Genes such as GPATCH3 [ 26 ] and GUCA1C [ 27 ] have been identified as candidate CG genes, although their role in the disease remains to be confirmed. Remarkable phenotypic variability is also present in CYP1B1 -associated glaucoma, ranging from mild adult-onset goniodysgenesis to agenesis of the Schlemm canal [ 18 , 28 ] and complete aniridia [ 29 ]. This phenomenon suggests the existence of modifier factors in the phenotypic outcome.…”

Section: Introductionmentioning

confidence: 99%

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

Alexandre-Moreno

Bonet-Fernández

Atienzar-Aroca

et al. 2021

IJMS

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CYP1B1 loss of function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle; however, the underlying molecular mechanisms are poorly understood. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in the 72% mRNA reduction with the residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Microphthalmia and jaw maldevelopment were observed in 23% of F0 somatic mosaic mutant larvae (144 hpf). These early phenotypes were not detected in cyp1b1-KO F3 larvae (144 hpf), but 27% of adult (four months) zebrafish exhibited uni- or bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in cyp1b1 mutants. Transcriptomic analyses of the offspring (seven dpf) of cyp1b1-KO progenitors with adult-onset craniofacial defects revealed functionally enriched differentially expressed genes related to extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids and fatty acids and oxidation–reduction processes that include several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of the phenotypes and molecular pathways associated with cyp1b1 LoF, with species dependency, and provides evidence for the dysregulation of extracellular matrix gene expression as one of the mechanisms underlying the pathogenicity associated with cyp1b1 disruption.

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“…Genes such as GPATCH3 [26] and GUCA1C [27] have been identified as candidate CG genes, although their role in the disease remains to be confirmed. Remarkable phenotypic variability is also present in CYP1B1-associated glaucoma, ranging from mild adult-onset goniodysgenesis to agenesis of the Schlemm canal [18,28] and complete aniridia [29]. This phenomenon suggests the existence of modifier factors in the phenotypic outcome.…”

Section: Introductionmentioning

confidence: 99%

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

Alexandre-Moreno

Bonet-Fernández

Atienzar-Aroca

et al. 2021

Preprint

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CYP1B1 loss-of-function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle and caused by poorly understood molecular mechanisms. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in a 72% mRNA reduction with residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Craniofacial defects and jaw maldevelopment were observed in 23% of somatic mosaic F0 crispant larvae (144 hpf). These early phenotypes were not detected in KO F3 larvae (144 hpf) but 27% of adult fishes (4 months) showed uni or bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in the cyp1b1 mutants. Transcriptomic analyses of the offspring (7dpf) of KO cyp1b1 progenitors with adult-onset craniofacial defects revealed that differentially expressed genes were functionally enriched in groups related with extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids, and fatty acids, and oxidation-reduction processes which included several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of phenotypes and molecular pathways associated with cyp1b1 LoF, with species-dependency, and provides evidence for dysregulation of extracellular matrix gene expression as one of the mechanisms underlaying pathogenicity associated with cyp1b1 disruption.

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A Novel CYP1B1 Mutation with Congenital Glaucoma and Total Aniridia

Abstract: CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.

Cited by 10 publications

References 2 publications

PAX6 gene analysis in Serbian patients with aniridia

PAX6 gene analysis in Serbian patients with aniridia

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

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