scholarly journals Deletions of distant regulatory sequences upstream of zebrafish pitx2 result in a range of ocular phenotypes

2019 ◽  
Author(s):  
Eric Weh ◽  
Elena Sorokina ◽  
Kathryn Hendee ◽  
Doug B. Gould ◽  
Elena V. Semina
Keyword(s):  
Anterior Segment ◽  
Genomic Region ◽  
Upstream Region ◽  
Regulatory Sequences ◽  
Coding Region ◽  
Enhancer Activity ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
Nearby Region ◽  
Vertebrate Eye

ABSTRACTDevelopment of the anterior segment of the vertebrate eye is a highly coordinated process. Genetic mutations in factors guiding this process result in Anterior Segment Dysgenesis (ASD), a spectrum of disorders affecting the iris, cornea, trabecular meshwork and/or other iridocorneal angle structures and associated with glaucoma. One of the first factors linked to ASD in humans was PITX2, a homeodomain containing transcription factor with a role in Axenfeld-Rieger syndrome (ARS). In addition to pathogenic alleles within the coding region of PITX2, deletions affecting the distant upstream region, but not PITX2 itself, have also been reported in ARS. Consistent with this, the distant upstream region was shown to contain multiple conserved elements (CE) with pitx2-related enhancer activity identified through studies in zebrafish. The two smallest human deletions reported to date encompass conserved elements 5-11 (ΔCE5-11) or 5-7 (ΔCE5-7). We previously reported the generation of ΔCE5-11 in zebrafish and we have now replicated the smallest deletion, ΔCE5-7, in the same model and studied the associated phenotype, expression, and DNA methylation profiles; we also performed further phenotypic examinations of the pitx2ΔCE5-11 fish. We show that the expression changes and phenotypes observed in the two lines are variable but that the severity generally correlates with the size of the deletion and the number of affected CEs; pitx2 promoter and a nearby region were hypermethylated in the pitx2ΔCE5-7 embryonic eyes. In addition, a subset of pitx2ΔCE5-11 animals were found to have a severe retinal phenotype suggesting that additional factors may modify the effects of this allele. These data provide further insight into functional sequences in the PITX2/pitx2 genomic region that coordinate PITX2/pitx2 expression during eye development and provide the basis for future studies into PITX2/pitx2 upstream regulators and modifiers.

scholarly journals Novel PITX2 Mutations including a Mutation Causing an Unusual Ophthalmic Phenotype of Axenfeld-Rieger Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Liqin Huang ◽  
Yong Meng ◽  
Xiangming Guo
Keyword(s):  
Genomic Dna ◽  
Anterior Segment ◽  
Dominant Negative ◽  
Chinese Patients ◽  
Dominant Negative Effect ◽  
Sequencing Analysis ◽  
Coding Region ◽  
Direct Dna Sequencing ◽  
Rieger Syndrome ◽  
Pitx2 Gene

Purpose. The aims of this study were to examine novel mutations in PITX2 and FOXC1 in Chinese patients with anterior segment dysgenesis (ASD) and to compare the clinical presentations of these mutations with previously reported associated phenotypes. Methods. Twenty-six unrelated patients with different forms of ASD were enrolled from our paediatric and genetic eye clinic. The ocular manifestations of both eyes of each patient were recorded. Genomic DNA was prepared from venous leukocytes. All coding exons of PITX2 and FOXC1 were amplified by polymerase chain reaction (PCR) from genomic DNA and subjected to direct DNA sequencing. Analysis of mutations in control subjects was performed by heteroduplex single-strand conformation polymorphism (SSCP) analysis. Results. Sequence analysis of the PITX2 gene revealed four mutations, including c.475_476delCT (P.L159VfsX39), c.64C > T (P.Q22X), c.296delG (P.R99PfsX56), and c.206G > A (P.R69H). The first three mutations were found to be novel. The c.475_476delCT (P.L159VfsX39) mutation, located at the 3′ end of the PITX2-coding region, was identified in a Chinese Axenfeld-Rieger syndrome (ARS) patient who presented with an unusual severe phenotype of bilateral aniridia. The clinical characteristics, including the severity and manifestations of the patient’s phenotype, were compared with reported PITX2-associated aniridia phenotypes of ARS in the literature. Conclusions. These results expand the mutation spectrum of the PITX2 gene in patients with ARS. The PITX2 gene may be responsible for a significant portion of ARS with additional systemic defects in the Chinese population. This is the first reported case of a mutation at the 3′ end of the PITX2-coding region extending the phenotypic consequences to bilateral aniridia. The traits of ARS could display tremendous variability in severity and manifestations due to the dominant-negative effect of PITX2. Our results further emphasize the importance of careful clinical and genetic analysis in determining mutation-disease associations and may lead to a better understanding of the role of PITX2 in ocular development.

scholarly journals Lgr4 in Ocular Development and Glaucoma

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Stefan Siwko ◽  
Li Lai ◽  
Jinsheng Weng ◽  
Mingyao Liu
Keyword(s):  
Anterior Segment ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Leucine Rich Repeat ◽  
Full Understanding ◽  
Ocular Development ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
G Protein Coupled ◽  
Retinal Vascularization

The leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4, also called GPR48) plays a key role in multiple developmental processes, and mice lackingLgr4display anterior segment dysgenesis leading to early-onset glaucomatous retinal ganglion cell loss as well as defective eyelid formation. This paper will review Lgr4 signaling and its regulation of the Axenfeld-Rieger syndrome genePitx2, a crucial developmental transcription factor. In addition, Wnt signaling plays an important role in eye development, with Norrin functioning to activate the Wnt receptor Frizzled 4 required for proper retinal vascularization. Recent discoveries identifying Lgr4 as a receptor for Norrin highlight the potential for Lgr4 function in retinal vascularization. Finally, several unanswered questions impeding a full understanding of Lgr4 in glaucoma are considered as avenues for further research.

scholarly journals Upstream region of OprD mutations in imipenem-resistant and imipenem-sensitive Pseudomonas aeruginosa isolates

2021 ◽  
Author(s):  
Masoumeh Kiani ◽  
Akram Astani ◽  
Nahid Rezaei Khozani ◽  
Mansoor Khaledi ◽  
Hamed Afkhami ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Point Mutations ◽  
Genomic Region ◽  
Upstream Region ◽  
Diffusion Method ◽  
Base Substitution ◽  
Coding Region ◽  
Biochemical Tests ◽  
Disk Diffusion Method ◽  
Study Results

Abstract The current study was aimed at investigating the prevalence of the mutations upstream of the oprD coding region and its promoters among imipenem-resistant and sensitive Pseudomonas aeruginosa isolated from educational hospitals in Yazd City, Iran. All isolates were identified by the conventional biochemical tests. Then, the antibiotic resistance of these isolates was determined using the disk diffusion method according to the CLSI guidelines. Also, the E.test was performed to determine the minimum inhibitory concentrations (MIC) of imipenem. The mutations of this gene were recognized by the amplification of this region and subsequently sequenced. Sequencing of the genomic region upstream of oprD these regions were done in the 29 clinical strains. Statistical analysis was done by the statistical software SPSS-18. Seventy (77.7%) of isolates had MIC ≥ 16 and were resistant to imipenem. Mutations of the upstream of the oprD gene and its promoters were seen in 25 (86.2%) isolates and 4 isolates had no mutation. One isolate had a base substitution A→Cat nt 25 in the coding region and this isolate had a point mutation leading to an amino acid change at positions 9 (I→L). Our study results indicated that none of the strains had mutation in Shine-Dalgarno and the point mutations were the most common mutations upstream of the oprD coding region among P. aeruginosa isolates. Mutations were observed in imipenem-resistant isolates and it seems this mechanism is effective in resistance of isolates to imipenem and this confirmed that the indiscriminate use of antibiotic should be controlled.

scholarly journals Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld–Rieger syndrome and anterior segment dysgenesis

2006 ◽  
Vol 15 (6) ◽  
pp. 905-919 ◽  
Author(s):  
Fred B. Berry ◽  
Matthew A. Lines ◽  
J. Martin Oas ◽  
Tim Footz ◽  
D. Alan Underhill ◽  
...  
Keyword(s):  
Anterior Segment ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
Functional Interactions ◽  
Gene Dose

scholarly journals Rieger anomaly and Axenfeld-Rieger syndrome: a rare anterior segment dysgenesis

2021 ◽  
Vol 106 (106(813)) ◽  
pp. 218-221
Author(s):  
J. Lacorzana ◽  
R. Rocha-da Silva ◽  
J.D. Sánchez-García ◽  
R. Rachwani-Anil ◽  
J.D. Martínez
Keyword(s):  
Anterior Segment ◽  
Dental Anomalies ◽  
Developmental Abnormalities ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
Dominant Disease ◽  
Systemic Manifestations ◽  
The One ◽  
Development And Management ◽  
Anterior Angle

Axenfeld Rieger Syndrome is anterior segment dysgenesis characterized by posterior embryotoxon and dysgenesis of the anterior chamber. Developmental abnormalities of the anterior angle cause increased resistance to outflow. Ocular hypertension is a complication in almost 50% of the cases. It is an autosomal dominant disease and its prevalence is between 50,000 and 100,000 newborns per year. The main associated affected genes are FOXC1 and PITX2, occurring in 40% of the cases. Axenfeld Rieger Syndrome can be associated with systemic manifestations such as dental anomalies (hypodontia and microdontia), facial anomalies (maxillary hypoplasia, telecanthus and hypertelorism), redundant paraumbilical skin, hypospadia, auditory and cardiac alterations. Within this syndrome, we distinguish different phenotypes, being the Rieger anomaly the one with least systemic affectation. We present three cases in different stages of the disease, which allow us to understand the development and management of this disorder.

scholarly journals Axenfeld-Rieger Syndrome: A Case Report with Literature Review

2021 ◽  
pp. 1-2
Author(s):  
Zakoun M ◽  
◽  
Belghmaidi S ◽  
Keyword(s):  
Case Report ◽  
Autosomal Dominant ◽  
Anterior Segment ◽  
Autosomal Dominant Disorder ◽  
Maxillary Hypoplasia ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
Ocular Manifestations ◽  
Systemic Manifestations ◽  
Anterior Angle

Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant disorder that has both systemic and ocular anterior segment dysgenesis. The ocular manifestations include posterior embryotoxon, iris and anterior angle abnomalies with a high risk of glaucoma and blindness. The systemic manifestations can include craniofacial abnomalies such as maxillary hypoplasia, hypodontia, oligodontia and microdont.

An unusual case of bilateral pigmented maculopathy and anterior segment dysgenesis

2017 ◽  
Vol 28 (2) ◽  
pp. 253-255
Author(s):  
Edward Bloch ◽  
Maria Pefkianaki ◽  
Jamil Hakim
Keyword(s):  
Unusual Case ◽  
Systemic Disease ◽  
Gene Array ◽  
Anterior Segment ◽  
Clinical Findings ◽  
Array Analysis ◽  
Anterior Segment Dysgenesis ◽  
Rieger Syndrome ◽  
Pigmented Lesions ◽  
Gene Array Analysis

Purpose: Pigmentary maculopathy can occur in the context of various inherited and acquired diseases. Anterior segment dysgenesis arises due to developmental anomalies and may be associated with systemic disease, as in Rieger syndrome. Case report: A 49-year-old woman presented with longstanding reduction in vision, evidence of anterior segment dysgenesis, and multiple discrete pigmented lesions throughout the macula bilaterally. Electroretinographic findings were consistent with severe macular dysfunction. Gene array analysis did not reveal any chromosomal imbalances or other specific abnormalities. Conclusions: This is a unique case of bilateral pigmentary maculopathy and anterior segment dysgenesis, with clinical findings that are not characteristic of previously reported disease.

scholarly journals Upstream region of OprD mutations in imipenem-resistant and imipenem-sensitive Pseudomonas isolates

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masoumeh Kiani ◽  
Akram Astani ◽  
Gilda Eslami ◽  
Mansoor Khaledi ◽  
Hamed Afkhami ◽  
...  
Keyword(s):  
Point Mutations ◽  
Genomic Region ◽  
Upstream Region ◽  
Diffusion Method ◽  
Base Substitution ◽  
Coding Region ◽  
Biochemical Tests ◽  
Disk Diffusion Method ◽  
Study Results ◽  
Yazd City

AbstractThe current study was aimed at investigating the prevalence of the mutations upstream of the oprD coding region and its promoters among imipenem-resistant and sensitive Pseudomonas aeruginosa isolated from educational hospitals in Yazd City, Iran. All isolates were identified by the conventional biochemical tests. Then, the antibiotic resistance of these isolates was determined using the disk diffusion method according to the CLSI guidelines. Also, the E.test was performed to determine the minimum inhibitory concentrations (MIC) of imipenem. The mutations of this gene were recognized by the amplification of this region and subsequently sequenced. Sequencing of the genomic region upstream of oprD these regions were done in the 29 clinical strains. Statistical analysis was done by the statistical software SPSS-18. Seventy (77.7%) of isolates had MIC ≥ 16 and were resistant to imipenem. Mutations of the upstream of the oprD gene and its promoters were seen in 25 (86.2%) isolates and 4 isolates had no mutation. One isolate had a base substitution A→Cat nt 25 in the coding region and this isolate had a point mutation leading to an amino acid change at positions 9 (I→L). Our study results indicated that none of the strains had mutation in Shine-Dalgarno and the point mutations were the most common mutations upstream of the oprD coding region among P. aeruginosa isolates. Mutations were observed in imipenem-resistant isolates and it seems this mechanism is effective in resistance of isolates to imipenem and this confirmed that the indiscriminate use of antibiotic should be controlled.

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