-
Cell Research Jan 2023Microphthalmia transcription factor (MITF) regulates melanocyte development and is the "lineage-specific survival" oncogene of melanoma. MITF is essential for melanoma...
Microphthalmia transcription factor (MITF) regulates melanocyte development and is the "lineage-specific survival" oncogene of melanoma. MITF is essential for melanoma initiation, progression, and relapse and has been considered an important therapeutic target; however, direct inhibition of MITF through small molecules is considered impossible, due to the absence of a ligand-binding pocket for drug design. Here, our structural analyses show that the structure of MITF is hyperdynamic because of its out-of-register leucine zipper with a 3-residue insertion. The dynamic MITF is highly vulnerable to dimer-disrupting mutations, as we observed that MITF loss-of-function mutations in human Waardenburg syndrome type 2 A are frequently located on the dimer interface and disrupt the dimer forming ability accordingly. These observations suggest a unique opportunity to inhibit MITF with small molecules capable of disrupting the MITF dimer. From a high throughput screening against 654,650 compounds, we discovered compound TT-012, which specifically binds to dynamic MITF and destroys the latter's dimer formation and DNA-binding ability. Using chromatin immunoprecipitation assay and RNA sequencing, we showed that TT-012 inhibits the transcriptional activity of MITF in B16F10 melanoma cells. In addition, TT-012 inhibits the growth of high-MITF melanoma cells, and inhibits the tumor growth and metastasis with tolerable toxicity to liver and immune cells in animal models. Together, this study demonstrates a unique hyperdynamic dimer interface in melanoma oncoprotein MITF, and reveals a novel approach to therapeutically suppress MITF activity.
Topics: Animals; Humans; Transcription Factors; Microphthalmos; Melanoma; Gene Expression Regulation; Oncogene Proteins; Microphthalmia-Associated Transcription Factor; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 36588115
DOI: 10.1038/s41422-022-00744-5 -
Acta Ophthalmologica Scandinavica Jun 1997Nanophthalmos is a rare congenital ocular malformation which is generally recognized at middle age when serious complications have already developed. In this report 7...
Nanophthalmos is a rare congenital ocular malformation which is generally recognized at middle age when serious complications have already developed. In this report 7 early diagnosed nanophthalmic cases are presented and diagnostic criteria, complications, inheritance and various modalities of treatment are discussed.
Topics: Adolescent; Adult; Anterior Chamber; Child; Child, Preschool; Combined Modality Therapy; Female; Follow-Up Studies; Glaucoma; Humans; Intraocular Pressure; Male; Microphthalmos; Pedigree; Visual Acuity
PubMed: 9253989
DOI: 10.1111/j.1600-0420.1997.tb00788.x -
Indian Journal of Ophthalmology Apr 2019Corticosteroids are known to cause many ocular and systemic side effects when administered by oral or parenteral routes. Corticosteroid induced systemic toxicity...
Corticosteroids are known to cause many ocular and systemic side effects when administered by oral or parenteral routes. Corticosteroid induced systemic toxicity secondary to topical steroid eye drops is rare. A 6-week-old, male infant was brought to our tertiary eye care center with bilateral congenital cataracts. The child underwent phacoaspiration with primary posterior capsulotomy without intraocular lens implantation in both eyes at an interval of 6 weeks. Child was initiated on topical betamethsone 0.1% eight times a day, tobramycin 0.3% six times a day, homatropine 2% twice a day, and carboxymethylcellulose 0.5% four times a day. Two and four weeks later he underwent surgical membranectomy in the right and left eye respectively followed by frequent use of topical steroids, initially given 1 hourly and then tapered weekly in the follow-up period. The patient showed increase in intraocular pressure and gain in body weight along with development of cushingoid habitus nearly 6 to 8 weeks after starting topical steroids. These side effects started weaning off following the reduction in dose of topical steroids, suggesting the role of the corticosteroid-related systemic side effects. This case highlights the serious systemic side effects secondary to increased frequency and duration of topical corticosteroid use in infancy. Hence, dosage of topical steroids should be adjusted in its therapeutic range to prevent their ocular and systemic side effects. Therefore, close monitoring is advocated for children using topical corticosteroids to prevent serious ocular and systemic side effects.
Topics: Administration, Topical; Betamethasone; Cataract; Cataract Extraction; Cushing Syndrome; Follow-Up Studies; Genetic Diseases, X-Linked; Glucocorticoids; Humans; Iatrogenic Disease; Infant; Male; Microphthalmos; Ophthalmic Solutions; Postoperative Complications
PubMed: 30900600
DOI: 10.4103/ijo.IJO_1091_18 -
Molecular Neurobiology Aug 2022The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain... (Review)
Review
The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain function, including autophagy-lysosomal pathway, lipid catabolism, and mitochondrial homeostasis. Among them, autophagy is one of the most relevant pathways in this frame; it is evolutionary conserved and crucial for cellular homeostasis. The dysregulation of MiTF/TFE proteins was shown to be involved in the development and progression of neurodegenerative diseases. Thus, the characterization of their function is key in the understanding of the etiology of these diseases, with the potential to develop novel therapeutics targeted to MiTF/TFE proteins and to the autophagic process. The fact that these proteins are evolutionary conserved suggests that their function and dysfunction can be investigated in model organisms with a simpler nervous system than the mammalian one. Building not only on studies in mammalian models but also in complementary model organisms, in this review we discuss (1) the mechanistic regulation of MiTF/TFE transcription factors; (2) their roles in different regions of the central nervous system, in different cell types, and their involvement in the development of neurodegenerative diseases, including lysosomal storage disorders; (3) the overlap and the compensation that occur among the different members of the family; (4) the importance of the evolutionary conservation of these protein and the process they regulate, which allows their study in different model organisms; and (5) their possible role as therapeutic targets in neurodegeneration.
Topics: Animals; Humans; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Brain; Lysosomes; Mammals; Microphthalmia-Associated Transcription Factor; Microphthalmos
PubMed: 35665902
DOI: 10.1007/s12035-022-02895-3 -
American Journal of Medical Genetics.... Aug 2022Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or...
Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.
Topics: Anophthalmos; Exome; Humans; Infant; Microphthalmos; Mutation, Missense; Exome Sequencing
PubMed: 35716026
DOI: 10.1002/ajmg.a.62874 -
Human Genetics Sep 2019Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important... (Review)
Review
Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases.
Topics: Animals; Chickens; Coloboma; Eye; Eye Abnormalities; Humans; Microphthalmos; Signal Transduction
PubMed: 29980841
DOI: 10.1007/s00439-018-1900-5 -
Eye (London, England) Mar 2023To compare the long-term efficacy and safety of combined phacoemulsification, anterior vitrectomy, and sclerectomy (triple procedure surgery, TS); combined...
OBJECTIVES
To compare the long-term efficacy and safety of combined phacoemulsification, anterior vitrectomy, and sclerectomy (triple procedure surgery, TS); combined phacoemulsification and anterior vitrectomy (double procedure surgery, DS); and filtering surgery (FS) in nanophthalmos with angle-closure glaucoma (NACG).
METHODS
Retrospective cohort study. Forty patients (44 eyes) diagnosed with NACG who underwent TS, DS, and FS were included. All eyes in the TS group and seven (47%) eyes in the DS group also underwent goniosynechialysis during the surgery. The main outcome measures (intraocular pressure [IOP], best-corrected visual acuity, complications, and second surgeries) were recorded at the early- (within 1 week) and late-stage (>3 months) follow-up.
RESULTS
The late-stage IOP was significantly lower in the TS (mean ± standard deviation: 13.29 ± 2.49 mm Hg) than in the DS (19.69 ± 6.97 mm Hg) and FS groups (27.57 ± 12.26 mm Hg, p < 0.001). More visual improvements were observed in the TS and DS groups than in the FS group at late-stage follow-up (p = 0.04). The complication rates in the TS, DS, and FS groups were 26%, 33%, and 70%, respectively (p = 0.046); the second surgery rates were 0%, 33%, and 60%, respectively (p < 0.001). In total, one, three, and six severe complications were observed in the TS, DS, and FS groups, respectively. The mean follow-up durations in the TS, DS, and FS groups were 18.89, 20.02, and 25.75 months, respectively.
CONCLUSIONS
NACG management remains challenging. TS presented relatively good clinical efficacy and safety with better postoperative IOP outcomes, lower complications, and second surgery rates among the three groups in eyes with NACG.
Topics: Humans; Phacoemulsification; Vitrectomy; Retrospective Studies; Sclerostomy; Trabeculectomy; Glaucoma; Intraocular Pressure; Treatment Outcome; Microphthalmos; Glaucoma, Angle-Closure
PubMed: 35383309
DOI: 10.1038/s41433-022-02039-w -
The British Journal of Ophthalmology Nov 2023Microphthalmia, anophthalmia and coloboma (MAC) are clinically and genetically heterogenous rare developmental eye conditions, which contribute to a significant...
BACKGROUND/AIMS
Microphthalmia, anophthalmia and coloboma (MAC) are clinically and genetically heterogenous rare developmental eye conditions, which contribute to a significant proportion of childhood blindness worldwide. Clear understanding of MAC aetiology and comorbidities is essential to providing patients with appropriate care. However, current management is unstandardised and molecular diagnostic rates remain low, particularly in those with unilateral presentation. To further understanding of clinical and genetic management of patients with MAC, we charted their real-world experience to ascertain optimal management pathways and yield from molecular analysis.
METHODS
A prospective cohort study of consecutive patients with MAC referred to the ocular genetics service at Moorfields Eye Hospital between 2017-2020.
RESULTS
Clinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families found 44% had additional ocular features (complex) and 34% had systemic involvement, most frequently intellectual/developmental delay (8/17). Molecular analysis of 39 families using targeted gene panels, whole genome sequencing and microarray comparative genomic hybridisation identified genetic causes in, 28% including novel variants in six known MAC genes (, , , , and ), and a molecular diagnostic rate of 33% for both bilateral and unilateral cohorts. New phenotypic associations were found for (bilateral sensorineural hearing loss) and (unilateral microphthalmia).
CONCLUSION
This study highlights the importance of thorough clinical and molecular phenotyping of MAC patients to provide appropriate multidisciplinary care. Routine genetic testing for both unilateral and bilateral cases in the clinic may increase diagnostic rates in the future, helping elucidate genotype-phenotype correlations and informing genetic counselling.
Topics: Humans; Anophthalmos; Microphthalmos; Coloboma; Prospective Studies; Eye Abnormalities; Eye Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 36192130
DOI: 10.1136/bjo-2022-321991 -
Hong Kong Medical Journal = Xianggang... Aug 2015Aplasia of the optic nerve is an extraordinarily rare congenital anomaly that affects one or both optic nerves and is associated with the absence of the central retinal...
Aplasia of the optic nerve is an extraordinarily rare congenital anomaly that affects one or both optic nerves and is associated with the absence of the central retinal vessel and retinal ganglion cells. We report a case of unilateral optic nerve aplasia in a 4-month-old infant who was found to have left microphthalmos on routine postnatal checkup. Family history, antenatal history, and systemic evaluation were unremarkable. Magnetic resonance imaging showed absent left optic nerve with left microphthalmos. The optic chiasm was present and slightly deviated towards the right side. The remaining cerebral and ocular structures were normal.
Topics: Blindness; Eye Diseases, Hereditary; Female; Humans; Infant; Microphthalmos; Optic Nerve Diseases; Retinal Diseases; Retinal Ganglion Cells; Retinal Vessels
PubMed: 26238135
DOI: 10.12809/hkmj144287 -
European Journal of Human Genetics :... Mar 2023ARHGAP35 has known roles in cell migration, invasion and division, neuronal morphogenesis, and gene/mRNA regulation; prior studies indicate a role in cancer in humans...
ARHGAP35 has known roles in cell migration, invasion and division, neuronal morphogenesis, and gene/mRNA regulation; prior studies indicate a role in cancer in humans and in the developing eyes, neural tissue, and renal structures in mice. We identified damaging variants in ARHGAP35 in five individuals from four families affected with anophthalmia, microphthalmia, coloboma and/or anterior segment dysgenesis disorders, together with variable non-ocular phenotypes in some families including renal, neurological, or cardiac anomalies. Three variants affected the extreme C-terminus of the protein, with two resulting in a frameshift and C-terminal extension and the other a missense change in the Rho-GAP domain; the fourth (nonsense) variant affected the middle of the gene and is the only allele predicted to undergo nonsense-mediated decay. This study implicates ARHGAP35 in human developmental eye phenotypes. C-terminal clustering of the identified alleles indicates a possible common mechanism for ocular disease but requires further studies.
Topics: Humans; Animals; Mice; Eye Abnormalities; Microphthalmos; Anophthalmos; Coloboma; Phenotype; Mutation; Repressor Proteins; Guanine Nucleotide Exchange Factors
PubMed: 36450800
DOI: 10.1038/s41431-022-01246-z