Explore the vast range of titles available.

Axenfeld–Rieger syndrome (ARS) is an uncommon manifestation of anterior segment development dysregulation. We recruited a two-generation Chinese family with hereditary ARS, which manifested as posterior embryotoxon, corneal leucoplakia, ectopic pupil, and extensive iris stromal atrophy with iridocorneal adhesion. Whole-exome sequencing (WES) was utilized for the initial screening, followed by Sanger sequencing to identify pathogenic gene mutations. A novel missense variant in FOXC1 (c.382C > T, p.H128Y) was identified. The FOXC1 protein is highly evolutionarily conserved. The potential effects of this mutation on protein structure were studied using 3D modelling and molecular dynamics (MD) simulation techniques. 3D modelling revealed that the mutation altered the conformation of the FOXC1 protein. The MD results suggested that the mutation could reduce the stability of the protein structure. Western blotting revealed that the expression of the mutant FOXC1 (c.382C > T, p.H128Y) was lower than that of the wild type. In summary, a novel FOXC1 variant was discovered within a Chinese family with ARS, broadening the spectrum of ARS mutations. This study also elucidated the underlying mechanisms by which FOXC1 gene deficiency causes ARS.

Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited. Histone modifications in cancer can contribute to pathogenesis. Here, the authors demonstrate that targeting epigenetic modifier Ezh2 hinders metastatic behaviour in Luminal B breast cancer models, and highlight a mechanism where Ezh2 contributes to metastatic behaviour by repression of FOXC1.

Purpose To determine the common gene mutation in patients with primary congenital glaucoma (PCG) in the Southeast region of Turkey via genetic analysis and to evaluate whether there were other gene mutations in these patients. Methods A total of 25 patients with PCG were included in this study. We performed sequence analysis including all exons of cytochrome p450 1B1 ( CYP1B1 ), myocilin ( MYOC ), forkhead box C1 ( FOXC1 ), and paired-like homeodomain 2 ( PITX2 ) genes of the obtained samples. Further, we analyzed the results using the Nextgen analysis program. Results The CYP1B1 gene mutation was detected in 20 (80%) of 25 patients, and FOXC1 gene mutation was detected in one (4%) patient. The mutation site of nine (45%) of the 20 CYP1B1 genes was found in the second exon. The pathogenic variant (p.Gly61Glu) was observed in 12 (60%) patients (in the first and second exons); the mutation type of six (50%) of these patients was homozygous. The mutation site of one patient with FOXC1 gene mutation was found to be in the first exon; its pathogenic variant was p.Met400lle. The mutation type in this gene was observed to be heterozygous. Lastly, there were no mutations in the MYOC, FOXC1 , and PITX2 genes in combination with the CYP1B1 gene mutation. Conclusion The most common cause of PCG in our region is the CYP1B1 gene mutation, and the most frequent pathogenic variant is c.182G > A (p.Gly61Glu). We also determined that the CYP1B1 gene mutation was alone and did not occur with other gene mutations ( MYOC , FOXC1 , and PITX2 ).

Purpose To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. Study design Molecular genetic analysis. Methods Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B , FOXC1 , and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). Results For CYP1B1 , we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1- , FOXC1- , and MYOC- negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. Conclusions Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.

Background Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant hereditary disease characterized primarily by maldevelopment of the anterior segment of both eyes, accompanied by developmental glaucoma, and other congenital anomalies. FOXC1 and PITX2 genes play important roles in the development of ARS. Case presentation The present report describes a 7-year-old boy with iris dysplasia, displaced pupils, and congenital glaucoma in both eyes. The patient presented with a congenital atrial septal defect and sublingual cyst. The patient’s family has no clinical manifestations. Next generation sequencing identified a pathogenic heterozygous missense variant in FOXC1 gene (NM_001453:c. 246C>A, p. S82R) in the patient. Sanger sequencing confirmed this result, and this mutation was not detected in the other three family members. Conclusion To the best of our knowledge, the results of our study reveal a novel mutation in the FOXC1 gene associated with ARS.

Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left–right axis, which provides vital cues for correct organ formation and function. Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld–Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left–right patterning can cause congenital heart defects, we investigated in zebrafish whether foxc1 contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated foxc1a and foxc1b mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in foxc1a−/−; foxc1b−/− homozygotes. Similarly, double homozygotes exhibit isomerism of the liver and pancreas, which are key features of abnormal gut situs. Placement of the asymmetric visceral organs relative to the midline was also perturbed by mRNA overexpression of foxc1a and foxc1b. In addition, an analysis of the left–right patterning components, identified in the lateral plate mesoderm of foxc1 mutants, reduced or abolished the expression of the NODAL antagonist lefty2. Together, these data reveal a novel contribution from foxc1 to left–right patterning, demonstrating that this role is sensitive to foxc1 gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld–Rieger syndrome patients.

Background The main features of Axenfeld–Rieger Syndrome (ARS) are ocular, auditory, neurological, and morphological brain abnormalities. Mutations in forkhead box protein C1 (FOXC1) are among the responsible genes causing ARS, but neuropsychiatric features have rarely been reported. The case of an ARS patient (a 77‐year‐old man) with delusions of jealousy and impairment of working memory, in addition to the main clinical features, glaucoma and leukoencephalopathy, is presented. Methods The mutation in the patient's genome was found with whole exome sequencing and in silico analysis using PolyPhen‐2 and SIFT. Furthermore, AlphaFold2 and PyMOL were used to predict the protein structure based on the mutation. Results A novel mutation at the forkhead domain of FOXC1 gene (c.408C>A, p.Phe136Leu) was found and confirmed in the patient's family, and it was predicted to cause protein damage; the SIFT score was 0, meaning deleterious, and the PolyPhen2 result also indicated damaging (score: 0.997). The predicted protein structure based on the novel mutation was different from that of the native structure. In the literature review, 6 of 95 (6.3%) cases showed neuropsychiatric features. Of them, 5 of 6 (83.3%) mutations were located in the forkhead domain. Conclusion A novel mutation was found in the FOXC1 gene (c.408C>A, p.Phe136Leu), which possibly induces delusions of jealousy and impairment of working memory, as well as features of ARS, by changing the protein structure. Mutations in that domain of the FOXC1 gene may be important not only for ocular abnormalities but also for brain function. The proband (II‐3) and his son (III‐3) have ARS by whole exome sequencing. The audiogram shows bilateral sensorineural hearing loss (red, right ear; blue, left ear). Brain magnetic resonance imaging data from the patient (T2‐weighted‐fluid‐attenuated inversion recovery). Representative dopamine active transporter single photon emission computed tomography and 123I‐MIBG myocardial scintigraphy show normal patterns.

(1) Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, the symptoms of which include both ocular and systemic abnormalities. In the studied subjects, the cornea was significantly opacified with peripheral scarring neovascularization, which is not specific to this syndrome. A suspicion of incorrect diagnosis was raised despite an initial diagnosis of a bilateral Chandler syndrome. (2) In order to provide the proper diagnosis, a DNA sequencing genetic test was conducted with three sisters carrying the presence of a genome imbalance in the FOXC1 gene. The aim of this study is to report a case of a Polish family with a novel gene mutation and its relation with ARS. (3) Our findings implicate the novel deletion of the FOXC1 gene in the pathogenesis of ARS in the affected family. The phenotypic variability observed, including differences in corneal and systemic anomalies, underscores the importance of genetic testing and suggests the influence of non-genetic factors on ARS manifestation.

Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.

Key Points Mutations that lead to clinically relevant eye phenotypes (such as anophthalmia, microphthalmia, aniridia, coloboma and cataract) highlight important steps in the development of this organ. This information allows us to establish a genetic hierarchy in which genes such as PAX6 , SIX3 and SOX2 lie at the top, other genes (such as FOXC1 , FOXE3 , PITX3 and MAF ) function downstream and tissue-specific genes such as the crystallin-encoding genes are the final targets. The ongoing and rapidly increasing characterization of mutations in humans and mice indicates that the frequency of mutations that lead to eye defects is not randomly distributed among the genes that are involved in eye development: some genes (including PAX6 , PAX2 and CRYG ) are frequently affected by mutations, whereas others are not targeted either by spontaneous or experimentally induced mutations in the mouse. Allelic series of mutations show that similar clinical phenotypes might be caused by mutations in different genes; by contrast, mutations in the same gene do not necessarily lead to the same phenotype, which indicates the importance of as yet unknown modulators of gene expression or function. The detailed molecular analysis of allelic series of mutations will also allow detailed genotype–phenotype correlations to be made, which should uncover the function of particular domains of the mutated proteins. The mature eye is a complex organ that develops through a highly organized process during embryogenesis. Alterations in its genetic programming can lead to severe disorders that become apparent at birth or shortly afterwards; for example, one-half of the cases of blindness in children have a genetic cause. This review outlines the genetic basis of eye development, as determined by mutation analysis in patients and in model organisms. A better understanding of how this intricate organ develops at the genetic and cellular level is central to our understanding of the pathologies that afflict it.