-
Journal of Clinical Medicine Apr 2024Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo... (Review)
Review
Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial-mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld-Rieger syndrome; cardiac-vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children.
PubMed: 38673496
DOI: 10.3390/jcm13082223 -
JCI Insight Apr 2024Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity....
Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.
Topics: Animals; Female; Humans; Male; Mice; Anterior Eye Segment; DNA, Intergenic; Enhancer Elements, Genetic; Eye Abnormalities; Eye Diseases, Hereditary; Homeobox Protein PITX2; Homeodomain Proteins; Mice, Knockout; Pedigree; Transcription Factors
PubMed: 38592784
DOI: 10.1172/jci.insight.177032 -
Investigative Ophthalmology & Visual... Apr 2024Axenfeld-Rieger syndrome (ARS) is characterized by ocular anomalies including posterior embryotoxon, iridocorneal adhesions, corectopia/iris hypoplasia, and...
PURPOSE
Axenfeld-Rieger syndrome (ARS) is characterized by ocular anomalies including posterior embryotoxon, iridocorneal adhesions, corectopia/iris hypoplasia, and developmental glaucoma. Although anterior segment defects and glaucoma contribute to decreased visual acuity, the role of potential posterior segment abnormalities has not been explored. We used high-resolution retinal imaging to test the hypothesis that individuals with ARS have posterior segment pathology.
METHODS
Three individuals with FOXC1-ARS and 10 with PITX2-ARS completed slit-lamp and fundus photography, optical coherence tomography (OCT), OCT angiography, and adaptive optics scanning light ophthalmoscopy (AOSLO). Quantitative metrics were compared to previously published values for individuals with normal vision.
RESULTS
All individuals demonstrated typical anterior segment phenotypes. Average ganglion cell and inner plexiform layer thickness was lower in PITX2-ARS, consistent with the glaucoma history in this group. A novel phenotype of foveal hypoplasia was noted in 40% of individuals with PITX2-ARS (but none with FOXC1-ARS). Moreover, the depth and volume of the foveal pit were significantly lower in PITX2-ARS compared to normal controls, even excluding individuals with foveal hypoplasia. Analysis of known foveal hypoplasia genes failed to identify an alternative explanation. Foveal cone density was decreased in one individual with foveal hypoplasia and normal in six without foveal hypoplasia. Two individuals (one from each group) demonstrated non-foveal retinal irregularities with regions of photoreceptor anomalies on OCT and AOSLO.
CONCLUSIONS
These findings implicate PITX2 in the development of the posterior segment, particularly the fovea, in humans. The identified posterior segment phenotypes may contribute to visual acuity deficits in individuals with PITX2-ARS.
Topics: Humans; Retina; Eye Abnormalities; Eye Diseases, Hereditary; Corneal Diseases; Glaucoma; Anterior Eye Segment
PubMed: 38587439
DOI: 10.1167/iovs.65.4.20 -
Investigative Ophthalmology & Visual... Mar 2024Intraflagellar transport 46 (IFT46) is an integral subunit of the IFT-B complex, playing a key role in the assembly and maintenance of primary cilia responsible for...
PURPOSE
Intraflagellar transport 46 (IFT46) is an integral subunit of the IFT-B complex, playing a key role in the assembly and maintenance of primary cilia responsible for transducing signaling pathways. Despite its predominant expression in the basal body of cilia, the precise role of Ift46 in ocular development remains undetermined. This study aimed to elucidate the impact of neural crest (NC)-specific deletion of Ift46 on ocular development.
METHODS
NC-specific conditional knockout mice for Ift46 (NC-Ift46F/F) were generated by crossing Ift46F mice with Wnt1-Cre2 mice, enabling the specific deletion of Ift46 in NC-derived cells (NCCs). Sonic Hedgehog (Shh) and Notch signaling activities in NC-Ift46F/F mice were evaluated using Gli1lacZ and CBF:H2B-Venus reporter mice, respectively. Cell fate mapping was conducted using ROSAmTmG reporter mice.
RESULTS
The deletion of Ift46 in NCCs resulted in a spectrum of ocular abnormalities, including thickened corneal stroma, hypoplasia of the anterior chamber, irregular iris morphology, and corneal neovascularization. Notably, this deletion led to reduced Shh signal activity in the periocular mesenchyme, sustained expression of key transcription factors Foxc1, Foxc2 and Pitx2, along with persistent cell proliferation. Additionally, it induced increased Notch signaling activity and the development of ectopic neovascularization within the corneal stroma.
CONCLUSIONS
The absence of primary cilia due to Ift46 deficiency in NCCs is associated with anterior segment dysgenesis (ASD) and corneal neovascularization, suggesting a potential link to Axenfeld-Rieger syndrome, a disorder characterized by ASD. This underscores the pivotal role of primary cilia in ensuring proper anterior segment development and maintaining an avascular cornea.
Topics: Mice; Animals; Cilia; Neural Crest; Corneal Neovascularization; Hedgehog Proteins; Cornea; Mice, Knockout; Cytoskeletal Proteins; Eye Abnormalities
PubMed: 38517430
DOI: 10.1167/iovs.65.3.30 -
BioRxiv : the Preprint Server For... Feb 2024Terminal selectors are transcription factors that control neuronal identity by regulating the expression of key effector molecules, such as neurotransmitter (NT)...
Terminal selectors are transcription factors that control neuronal identity by regulating the expression of key effector molecules, such as neurotransmitter (NT) biosynthesis proteins, ion channels and neuropeptides. Whether and how terminal selectors control neuronal connectivity is poorly understood. Here, we report that UNC-30 (PITX2/3), the terminal selector of GABA motor neuron identity in , is required for NT receptor clustering, a hallmark of postsynaptic differentiation. Animals lacking or the short isoform of the MN-secreted synapse organizer ( ), display severe GABA receptor type A (GABA R) clustering defects in postsynaptic muscle cells. Mechanistically, UNC-30 acts directly to induce and maintain transcription of and GABA biosynthesis genes (e.g., , ). Hence, UNC-30 controls GABA R clustering on postsynaptic muscle cells and GABA biosynthesis in presynaptic cells, transcriptionally coordinating two critical processes for GABA neurotransmission. Further, we uncover multiple target genes and a dual role for UNC-30 both as an activator and repressor of gene transcription. Our findings on UNC-30 function may contribute to our molecular understanding of human conditions, such as Axenfeld-Rieger syndrome, caused by PITX2 and PITX3 gene mutations.
PubMed: 38405977
DOI: 10.1101/2024.02.14.580278 -
Ear, Nose, & Throat Journal Feb 2024
PubMed: 38321760
DOI: 10.1177/01455613241229955 -
Taiwan Journal of Ophthalmology 2023Axenfeld-Rieger spectrum is a range of anterior segment dysgenesis (ASD) phenotypes often related to heterozygous pathogenic variants in the ocular transcription factor...
Axenfeld-Rieger spectrum is a range of anterior segment dysgenesis (ASD) phenotypes often related to heterozygous pathogenic variants in the ocular transcription factor genes or . Microcornea with myopic chorioretinal atrophy, a less common ASD, is distinct, recognizable, and secondary to biallelic pathogenic variants in the metalloproteinase gene . This report describes the case of a boy with -related ASD that was mistaken for Axenfeld-Rieger syndrome and highlights distinguishing features.
PubMed: 38249507
DOI: 10.4103/tjo.TJO-D-23-00034 -
Taiwan Journal of Ophthalmology 2023Axenfeld-Rieger syndrome (ARS) is a rare autosomal-dominant neurocristopathy that presents with a variety of classical ocular and systemic findings. The pathophysiology... (Review)
Review
Axenfeld-Rieger syndrome (ARS) is a rare autosomal-dominant neurocristopathy that presents with a variety of classical ocular and systemic findings. The pathophysiology of the disease involves anterior segment dysgenesis, and patients may present with ophthalmic complications early in life, including secondary glaucoma, high refractive errors, amblyopia, and permanent visual damage. There are a limited number of studies in the literature that focus primarily on pediatric patients with ARS. The purpose of this article was to review the current literature on clinical presentation, genetic associations, diagnosis, secondary complications, and treatment of ARS in pediatric patients. Evaluating the essential clinical aspects of the disease in children may allow for earlier diagnosis and treatment and prevent visual morbidity from amblyopia and secondary glaucoma that may result in permanent visual damage.
PubMed: 38249500
DOI: 10.4103/tjo.TJO-D-23-00089 -
Dentistry Journal Dec 2023The aim of this systematic review was to describe the clinical and genetic features of syndromes showing oligodontia as a sign. The review was performed according to the... (Review)
Review
The aim of this systematic review was to describe the clinical and genetic features of syndromes showing oligodontia as a sign. The review was performed according to the PRISMA 2020 checklist guidelines, and the search was conducted using PubMed, Scopus, Lilacs, Web of science, Livivo, and EMBASE and supplemented by a gray literature search on Google Scholar and ProQuest, applying key terms relevant to the research questions. The systematic review identified 47 types of syndromes in 83 studies, and the most common was hypohidrotic ectodermal dysplasia, which was reported in 24 patients in 22 studies. Other common syndromes that reported oligodontia included Axenfeld-Rieger syndrome, Witkop's syndrome, Ellis-van Creveld syndrome, blepharocheilodontic syndrome, and oculofaciocardiodental syndrome. The X-linked mode of inheritance was the most reported (n = 13 studies), followed by the autosomal dominant (n = 13 studies). The review describes the main syndromes that may have oligodontia as a clinical sign and reinforces the need for orodental-facial examining for adequate diagnosis and treatment of the affected patients. Molecular analysis in order to better understand the occurrence of oligodontia is imperative.
PubMed: 38132417
DOI: 10.3390/dj11120279