Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.425
Filtrar
1.
Orv Hetil ; 160(37): 1447-1454, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31495190

RESUMO

Myotonic dystrophy is one of the most common, autosomal dominantly inherited adult-onset muscle disorders. Two types of the disease are known: type 1 is characterized by distal weakness and myotonia, but type 2 is associated with proximal weakness and milder clinical course. It is also called as Steinert Disease, which affects the heart conduction system, the internal secretional glands, the ocular lens as well as carbohydrate-, fat metabolism and gonadal functions. These systemic symptoms have high impact on the quality of life and might impact on patients' survival. Here we would like to emphasize these clinical conditions and the diagnostic possibilities. We hope our recommendations can help neurologists and general practitioners to achieve an optimal and individual care for patients suffering from this muscle disease. Orv Hetil. 2019; 160(37): 1447-1454.


Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Distrofia Miotônica/diagnóstico , Adulto , Catarata/genética , Humanos , Resistência à Insulina/genética , Músculos/fisiopatologia , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Doenças do Sistema Nervoso , Qualidade de Vida , Expansão das Repetições de Trinucleotídeos
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 697-700, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302914

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with congenital cataracts. METHODS: Clinical data and peripheral blood samples were collected for the pedigree. Following extraction of genomic DNA, whole exome sequencing was carried out to detect genetic variants. Candidate variants were verified by familial co-segregation analysis and Sanger sequencing. Bioinformatics analysis was carried out to predict the function of mutant genes. RESULTS: By comparing variants identified among affected and unaffected individuals, a heterozygous variant, c.110 G>C (p.R37P), was identified in exon 2 of the CRYGC gene among all patients, which also matched the criteria for potential disease-causing mutations. The result was confirmed by Sanger sequencing. CONCLUSION: The c.110G>C variant of the CRYGC gene probably underlay the congenital cataracts in this pedigree.


Assuntos
Catarata/congênito , Catarata/genética , gama-Cristalinas/genética , Grupo com Ancestrais do Continente Asiático , China , Heterozigoto , Humanos , Mutação , Linhagem
3.
Gene ; 710: 170-177, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31153886

RESUMO

Covalently closed, single-stranded circular RNAs (circRNAs) are a class of newly discovered endogenous RNAs involved in the pathological process of various types of diseases through sponging microRNAs (miRNAs). However, the role of circRNAs in diabetic cataract (DC) is unclear. Our previous studies have demonstrated that miR-204-5p was expressed more lowly in DC than the normal controls, but whether it relates to the sponge function of circRNAs remains unknown. This study aimed to identify differentially expressed circRNAs in DC tissues and investigate the interaction between circRNAs and miR-204-5p in the development of cataract. RNA-sequencing based circRNA expression profiling was determined in DC lens tissues as well as transparent lens tissues, and 1063 circRNAs were significantly differentially expressed in the DC group compared to the normal control group (p ≤ 0.05, fold change ≥ 2.0). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to predict the function of these differentially expressed circRNAs, and the top ten enriched GO entries and KEGG pathways were annotated. Expression levels of the two candidate circRNAs having conserved interaction with miR-204-5p were validated by qRT-PCR, showing that the change direction of these circRNAs was consistent with the RNA-sequencing data. Moreover, circKMT2E was up-regulated more than two folds in DC lens tissues compared with normal tissues, exhibiting an expression trend opposite to miR-204-5p. Bio-informatics analysis showed that there were totally four seed sequences of circKMT2E on hsa-miR-204-5p. Thus, we speculated that circKMT2E may function as a sponge molecule of miR-204-5p and play a role in the pathogenesis of DC. Although the exact mechanisms need further validation, our study found that the differentially expressed circRNAs was involved in the pathogenesis of DC, which can provide a new target for non-surgical treatment of DC.


Assuntos
Catarata/genética , Complicações do Diabetes/genética , MicroRNAs/genética , RNA/genética , Regulação para Cima , Idoso , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Cristalino/química , Cristalino/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA
4.
Gene ; 704: 113-120, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974196

RESUMO

Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12, an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12.


Assuntos
Códon sem Sentido , Monoacilglicerol Lipases/genética , Síndromes de Usher/genética , Adulto , Idoso , Ataxia/genética , Ataxia/patologia , Catarata/genética , Catarata/patologia , Criança , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polineuropatias/genética , Polineuropatias/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Síndromes de Usher/patologia , Sequenciamento Completo do Exoma
5.
FEBS Open Bio ; 9(5): 840-850, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31034164

RESUMO

Connexins (Cx) are proteins that form cell-to-cell gap junction channels. A mutation at position 188 in the second extracellular loop (E2) domain of hCx46 has been linked to an autosomal dominant zonular pulverulent cataract. As it is dominantly inherited, it is possible that the mutant variant affects the co-expressed wild-type Cx and/or its interaction with other cellular components. Here, we proposed to use concatenated hCx46wt-hCx46N188T and hCx46N188T-hCx46wt to analyze how hCx46N188T affected co-expressed hCx46wt to achieve a dominant inheritance. Heterodimer hCx46wt-hCx46N188T formed fewer gap junction plaques compared to homodimer hCx46wt-hCx46wt, while the hCx46N188T-hCx46N188T homodimer formed almost no gap junction plaques. Dye uptake experiments showed that hemichannels of concatenated variants were similar to hemichannels of monomers. Molecular dynamics simulations revealed that for docking, the N188 of a protomer was engaged in hydrogen bonds (HBs) with R180, N189, and D191 of the counterpart protomer of the adjacent hemichannel. T188 suppressed the formation of HBs between protomers. Molecular dynamics simulations of an equimolar hCx46wt/hCx46N188T gap junction channel revealed a reduced number of HBs between protomers, suggesting reduction of gap junction channels between lens fibers co-expressing the variants.


Assuntos
Conexinas/genética , DNA Concatenado/genética , Simulação de Dinâmica Molecular , Mutação/genética , Catarata/congênito , Catarata/genética , Conexinas/metabolismo , DNA Concatenado/metabolismo , Junções Comunicantes/genética , Células HeLa , Humanos
6.
Mol Med Rep ; 19(5): 4419-4424, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942463

RESUMO

Nance­Horan syndrome (NHS) is a rare X­linked disorder with various clinical manifestations. The present study aimed to identify the pathogenic mutation causing NHS in a three­generation Chinese family with 4 individuals presenting primarily with congenital cataracts. The genomic DNA of 5 individuals was collected, and family history and clinical information were recorded. Whole exome sequencing was performed on the proband, and candidate mutations were filtered by a series of screening processes and validated by Sanger sequencing. The identified pathogenic mutation was confirmed by co­segregation analysis. Finally, a novel frameshift mutation (NM_001291867.1: c.302dupA; p.Ala102fs) was identified in the NHS actin remodeling regulator (NHS) gene, which co­segregated with congenital cataracts in this family. Carrier females exhibited similar but milder clinical symptoms compared with the affected male. These clinical symptoms were consistent with the phenotypic features of the NHS­associated disease, NHS. In summary, the present study identified a novel NHS mutation in a Chinese family with atypical NHS; the results broaden the known pathogenic mutation spectrum of NHS and will aid in the genetic counseling of patients with NHS. The data from the present study also suggest that genetic analysis may be required for the diagnosis of this disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Catarata/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Adulto , Catarata/genética , Catarata/patologia , Pré-Escolar , Feminino , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Linhagem , Anormalidades Dentárias/patologia , Sequenciamento Completo do Exoma
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(4): 380-383, 2019 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-30950031

RESUMO

OBJECTIVE: To assess the association of Eph-receptor tyrosinekinase-type A2 (EphA2) gene polymorphisms with susceptibility to age-related cataract (ARC) among ethnic Han Chinese from Hubei Province. METHODS: 280 patients with cortical ARC and 200 healthy controls were recruited. Polymorphisms at four loci (rs3768293, rs3754334, rs477558 and rs7548209) of the EphA2 gene were detected by PCR-restriction fragment length polymorphism (PCR-RELP) assay. Allelic and genotypic frequencies of the two groups were compared. RESULTS: Compared with the control group, the AA genotype of rs3768293 locus was more common, while the AC genotype was much rarer (P< 0.05). No significant difference was found in allelic and genotypic frequencies of rs3754334 locus between the two groups (P> 0.05). The AA genotype of the rs477558 locus was more common in the patient group, while the AG genotype was much rarer (P< 0.05). The genotype GG of the rs7548209 locus was more common in the patient group, while the CG genotype was rarer (P< 0.05), though no significant difference in allelic or haplotypic frequencies between the two groups (P> 0.05). CONCLUSION: Polymorphisms of rs477558, rs7548209 and rs3768293 loci of the EphA2 gene are associated with susceptibility to ARC among ethnic Han Chinese from Hubei province.


Assuntos
Catarata , Polimorfismo Genético , Grupo com Ancestrais do Continente Asiático , Catarata/genética , China , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos
8.
PLoS Genet ; 15(4): e1008088, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034465

RESUMO

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Transtornos da Motilidade Ciliar/genética , Nanismo/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
9.
Cell Mol Life Sci ; 76(10): 1935-1945, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830238

RESUMO

Rab18 is one of the small number of conserved Rab proteins which have been traced to the last eukaryotic common ancestor. It is found in organisms ranging from humans to trypanosomes, and localizes to multiple organelles, including most notably endoplasmic reticulum and lipid droplets. In humans, absence of Rab18 leads to a severe illness known as Warburg-Micro syndrome. Despite this evidence that Rab18 is essential, its role in cells remains mysterious. However, recent studies identifying effectors and interactors of Rab18, are now shedding light on its mechanism of action, suggesting functions related to organelle tethering and to autophagy. In this review, we examine the variety of roles proposed for Rab18 with a focus on new evidence giving insights into the molecular mechanisms it utilizes. Based on this summary of our current understanding, we identify priority areas for further research.


Assuntos
Retículo Endoplasmático/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Proteínas rab de Ligação ao GTP/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Autofagia/genética , Catarata/congênito , Catarata/genética , Catarata/metabolismo , Córnea/anormalidades , Córnea/metabolismo , Humanos , Hipogonadismo/genética , Hipogonadismo/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Microcefalia/genética , Microcefalia/metabolismo , Modelos Biológicos , Mutação , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Proteínas rab de Ligação ao GTP/genética
10.
Medicine (Baltimore) ; 98(11): e14803, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30882657

RESUMO

RATIONALE: The case with congenital macular coloboma and cataract was rarely reported, and the pathogenic gene of the disease is still not clear. Moreover, it is difficult to improve the visual acuity of the eye with this disease. PATIENT CONCERNS: An 11-year-old boy presented low visual acuity and horizontal nystagmus in both eyes. Ophthalmologic examination showed the patient with bilateral congenital coloboma and cataract. The visual acuity of the patient improved slightly after cataract surgery. Heterozygous mutations of frizzled-4 (FZD4) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) were identified by next-generation sequencing in this case. DIAGNOSIS: Congenital macular coloboma and cataract of both eyes. INTERVENTIONS: We performed the standard phacoemulsification and intraocular lens implantation on both eyes of the patient for the treatment of congenital cataract, and then followed up the fundus lesions regularly. OUTCOMES: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, but the vision of this patient was still very poor postoperatively. Furthermore, the heterozygous mutations of FZD4 and NOD2 were found in this patient. LESSONS: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, and heterozygous mutations of FZD4 and NOD2 may be involved in the occurrence of congenital macular coloboma and cataract.


Assuntos
Catarata , Coloboma , Receptores Frizzled/genética , Implante de Lente Intraocular/métodos , Macula Lutea/anormalidades , Proteína Adaptadora de Sinalização NOD2/genética , Facoemulsificação/métodos , Catarata/congênito , Catarata/diagnóstico , Catarata/genética , Catarata/fisiopatologia , Criança , Coloboma/diagnóstico , Coloboma/genética , Coloboma/fisiopatologia , Coloboma/cirurgia , Técnicas de Diagnóstico Oftalmológico , Humanos , Macula Lutea/fisiopatologia , Macula Lutea/cirurgia , Masculino , Nistagmo Patológico/diagnóstico , Nistagmo Patológico/etiologia , Resultado do Tratamento , Acuidade Visual
11.
Mol Vis ; 25: 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820140

RESUMO

Purpose: To identify the mutation for Volkmann cataract (CTRCT8) at 1p36.33. Methods: The genes in the candidate region 1p36.33 were Sanger and parallel deep sequenced, and informative single nucleotide polymorphisms (SNPs) were identified for linkage analysis. Expression analysis with reverse transcription polymerase chain reaction (RT-PCR) of the candidate gene was performed using RNA from different human tissues. Quantitative transcription polymerase chain reaction (qRT-PCR) analysis of the GNB1 gene was performed in affected and healthy individuals. Bioinformatic analysis of the linkage regions including the candidate gene was performed. Results: Linkage analysis of the 1p36.33 CCV locus applying new marker systems obtained with Sanger and deep sequencing reduced the candidate locus from 2.1 Mb to 0.389 Mb flanked by the markers STS-22AC and rs549772338 and resulted in an logarithm of the odds (LOD) score of Z = 21.67. The identified mutation, rs763295804, affects the donor splice site in the long non-coding RNA gene RP1-140A9.1 (ENSG00000231050). The gene including splice-site junctions is conserved in primates but not in other mammalian genomes, and two alternative transcripts were shown with RT-PCR. One of these transcripts represented a lens cell-specific transcript. Meta-analysis of the Cross-Linking-Immuno-Precipitation sequencing (CLIP-Seq) data suggested the RNA binding protein (RBP) eIF4AIII is an active counterpart for RP1-140A9.1, and several miRNA and transcription factors binding sites were predicted in the proximity of the mutation. ENCODE DNase I hypersensitivity and histone methylation and acetylation data suggest the genomic region may have regulatory functions. Conclusions: The mutation in RP1-140A9.1 suggests the long non-coding RNA as the candidate cataract gene associated with the autosomal dominant inherited congenital cataract from CCV. The mutation has the potential to destroy exon/intron splicing of both transcripts of RP1-140A9.1. Sanger and massive deep resequencing of the linkage region failed to identify alternative candidates suggesting the mutation in RP1-140A9.1 is causative for the CCV phenotype.


Assuntos
Catarata/congênito , Cromossomos Humanos Par 1/química , Mutação , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Acetilação , Adulto , Sequência de Bases , Sítios de Ligação , Catarata/diagnóstico , Catarata/genética , Catarata/patologia , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Éxons , Família , Feminino , Genes Dominantes , Loci Gênicos , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/genética , Histonas/metabolismo , Humanos , Íntrons , Masculino , Metilação , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA , Processamento de RNA , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo
12.
Mol Vis ; 25: 118-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820147

RESUMO

Purpose: As the aging population is increasing, the incidence of age-related cataract is expected to increase globally. The surgical intervention, a treatment for cataract, still has complications and is limited to developed countries. In this study, we investigated whether the polyphenol-enriched fraction of Vaccinium uliginosum L. (FH) prevents cataract formation in Sprague-Dawley (SD) rat pups. Methods: Sixty rat pups were randomly divided into six groups: CTL, Se, FH40, FH80, FH120, and Cur80. The cataract was induced with subcutaneous injection of sodium selenite (18 µmol/kg bodyweight) on postnatal (P) day 10. All groups, except CTL, were injected with sodium selenite, and the FH40, FH80, and FH120 groups were given gastric intubation with FH40 mg/kg, 80 mg/kg, and 120 mg/kg on P9, P10, and P11. The Cur80 group was also given gastric intubation with curcumin 80 mg/kg on P9, P10, and P11. All rat pups were euthanized on P30. Results: Lens morphological analysis showed that FH dose-dependently inhibited cataract formation. In the Se group, soluble proteins were insolubilized, and the gene expression of the α-, ß-, and γ-crystallins was downregulated. However, FH treatment statistically significantly inhibited insolubilization of soluble proteins and downregulation of the gene expression of the α-, ß-, and γ-crystallins. In the Se group, the gene and protein levels of m-calpain were downregulated, which were attenuated with FH treatment. In addition, sodium selenite injection caused reduced antioxidant enzymes (superoxide dismutase (SOD) and glutathione peroxidase (GPx)), glutathione (GSH) depletion, and malondialdehyde (MDA) production in the lens. The administration of FH inhibited sodium selenite-induced oxidative stress in a dose-dependent manner. The mechanism of protection against oxidative stress by FH involves NF-E2-related factor (Nrf-2) and hemoxygenase-1 (HO-1). FH treatment inhibited decrease of Nrf-2 in the nucleus fraction and HO-1 in the cytosol fraction. Finally, the FH treatment protected poly (ADP)-ribose polymerase (PARP) from cleavage, determined with western blotting. Conclusions: FH showed a preventive effect against cataract formation by inhibiting m-calpain-mediated proteolysis and oxidative stress in the lens. These results suggest that FH could be a potential anticataract agent in age-related cataract.


Assuntos
Antioxidantes/farmacologia , Mirtilos Azuis (Planta)/química , Catarata/prevenção & controle , Proteínas do Olho/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Polifenóis/farmacologia , Animais , Animais Recém-Nascidos , Antioxidantes/isolamento & purificação , Calpaína/genética , Calpaína/metabolismo , Catarata/induzido quimicamente , Catarata/genética , Catarata/patologia , Proteínas do Olho/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Cristalino/efeitos dos fármacos , Cristalino/metabolismo , Cristalino/patologia , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Polifenóis/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Selenito de Sódio/administração & dosagem , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , alfa-Cristalinas/genética , alfa-Cristalinas/metabolismo , beta-Cristalinas/genética , beta-Cristalinas/metabolismo , gama-Cristalinas/genética , gama-Cristalinas/metabolismo
13.
Mol Vis ; 25: 129-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820148

RESUMO

Purpose: To identify the effects of a single copy deletion of Yap1 (Yap1 +/-) in the mouse eye, the ocular phenotypic consequences of Yap1 +/- were determined in detail. Methods: Complete ophthalmic examinations, as well as corneal esthesiometry, the phenol red thread test, intraocular pressure, and Fourier-domain optical coherence tomography were performed on Yap1 +/- and age-matched wild-type (WT) mice between eyelid opening (2 weeks after birth) and adulthood (2 months and 1 year after birth). Following euthanasia, enucleated eyes were characterized histologically. Results: Microphthalmia with small palpebral fissures, corneal fibrosis, and reduced corneal sensation were common findings in the Yap1 +/- mice. Generalized corneal fibrosis precluded clinical examination of the posterior structures. Histologically, thinning and keratinization of the corneal epithelium were observed in the Yap1 +/- mice in comparison with the WT mice. Distorted collagen fiber arrangement and hypercellularity of keratocytes were observed in the stroma. Descemet's membrane was extremely thin and lacked an endothelial layer in the Yap1 +/- mice. The iris was adherent to the posterior cornea along most of its surface creating a distorted contour. Most of the Yap1 +/- eyes were microphakic with swollen fibers and bladder cells. The retinas of the Yap1 +/- mice were normal at 2 weeks and 2 months of age, but the presence of retinal abnormalities, including retinoschisis and detachment, was markedly increased in the Yap1 +/- mice at 1 year of age. Conclusions: The results show that the heterozygous deletion of the Yap1 gene in mice leads to complex ocular abnormalities, including microphthalmia, corneal fibrosis, anterior segment dysgenesis, and cataract.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Catarata/genética , Anormalidades do Olho/genética , Microftalmia/genética , Fenótipo , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Catarata/diagnóstico por imagem , Catarata/metabolismo , Catarata/patologia , Substância Própria/diagnóstico por imagem , Substância Própria/metabolismo , Substância Própria/patologia , Lâmina Limitante Posterior/diagnóstico por imagem , Lâmina Limitante Posterior/metabolismo , Lâmina Limitante Posterior/patologia , Epitélio Anterior/diagnóstico por imagem , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Feminino , Fibrose , Expressão Gênica , Heterozigoto , Pressão Intraocular/fisiologia , Iris/diagnóstico por imagem , Iris/metabolismo , Iris/patologia , Masculino , Camundongos , Camundongos Knockout , Microftalmia/diagnóstico por imagem , Microftalmia/metabolismo , Microftalmia/patologia , Fosfoproteínas/deficiência , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Tomografia de Coerência Óptica , Tonometria Ocular
14.
Mol Med Rep ; 19(4): 3123-3131, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816539

RESUMO

The present study aimed to identify the disease­causing gene of a four­generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four­generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co­segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four­generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four­generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene­associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Catarata/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Mutação , Fatores de Transcrição/genética , Catarata/epidemiologia , Biologia Computacional/métodos , Feminino , Imunofluorescência , Regulação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Espaço Intracelular/metabolismo , Masculino , Ligação Proteica , Transporte Proteico , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma
15.
PLoS Genet ; 15(3): e1007605, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30856165

RESUMO

Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Genetic analysis of 85 unrelated "mutation negative" probands with Martsolf or Martsolf-like syndromes identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). Both probands were from multiplex families with a consistent, lethal and highly distinctive disorder; a Martsolf-like syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rI/dI) into RNA and DNA. In Itpa-null cells dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA without detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in proband-derived lymphoblastoid RNA. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA-and by implication rI production-correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.


Assuntos
Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/genética , Catarata/enzimologia , Catarata/genética , Hipogonadismo/enzimologia , Hipogonadismo/genética , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/genética , Pirofosfatases/deficiência , Animais , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Homozigoto , Humanos , Inosina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Embrionárias Murinas/enzimologia , Mutação , Linhagem , Pirofosfatases/genética , RNA/genética , RNA/metabolismo , Sequenciamento Completo do Exoma
16.
Invest Ophthalmol Vis Sci ; 60(4): 858-867, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30821811

RESUMO

Purpose: Investigate the effects of the absence of 17 amino acids at the C-terminal end of Aquaporin 0 (AQP0) on lens transparency, focusing property, and homeostasis. Methods: A knockin (KI) mouse model (AQP0ΔC/ΔC) was developed to express AQP0 only as the end-cleaved form in the lens. For this, AQP0 was genetically engineered as C-terminally end-cleaved with amino acids 1 to 246, instead of the full length 1 to 263 of the wild type (WT). After verifying the KI integration into the genome and its expression, the mouse model was bred for several generations. AQP0 KI homozygous (AQP0ΔC/ΔC) and heterozygous (AQP0+/ΔC) lenses were imaged and analyzed at different developmental stages for transparency. Correspondingly, aberrations in the lens were characterized using the standard metal grid focusing method. Data were compared with age-matched WT, AQP0 knockout (AQP0-/-), and AQP0 heterozygous (AQP0+/-) lenses. Results: AQP0ΔC/ΔC lenses were transparent throughout the embryonic development and until postnatal day 15 (P15) in contrast to age-matched AQP0-/- lenses, which developed cataract at embryonic stage itself. However, there was distortion aberration in AQP0ΔC/ΔC lens at P5; after P15, cataract began to develop and progressed faster surpassing that of age-matched AQP0-/- lenses. AQP0+/ΔC lenses were transparent even at the age of 1 year in contrast to AQP0+/- lenses; however, there was distortion aberration starting at P15. Conclusions: A specific distribution profile of intact and end-cleaved AQP0 from the outer cortex to the inner nucleus is required in the lens for establishing refractive index gradient to enable proper focusing without aberrations and for maintaining transparency.


Assuntos
Sequência de Aminoácidos/genética , Aquaporinas/genética , Catarata/genética , Proteínas do Olho/genética , Cristalino/patologia , Erros de Refração/genética , Deleção de Sequência/genética , Animais , Western Blotting , Catarata/embriologia , Catarata/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Erros de Refração/embriologia , Erros de Refração/fisiopatologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Transfecção
17.
BMC Med Genet ; 20(1): 41, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890130

RESUMO

BACKGROUND: Congenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported. CASE PRESENTATION: A 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband's mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband's daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family. CONCLUSIONS: This is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.


Assuntos
Catarata/congênito , Conexinas/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Catarata/genética , China , Comorbidade , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Adulto Jovem
18.
BMC Med Genet ; 20(1): 42, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894134

RESUMO

BACKGROUND: Congenital cataract is the most common cause of blindness among children worldwide. The aim of this study was to identify causative mutations in a Chinese family with isolated autosomal dominant posterior subcapsular cataract. METHODS: The proband and her parents underwent full ophthalmological examinations. DNA was extracted from the participants' peripheral venous blood. The mutation was identified via panel-based next-generation sequencing (NGS) and was validated via Sanger sequencing. RESULTS: Posterior subcapsular lenticular opacity was observed in both of the proband's eyes. The novel deletion mutation c.797_814del, p.Ser266_Ala271del in the PITX3 gene was identified in the proband and her father. This mutation is located within the otp/aristaless/rax (OAR) domain at the COOH-terminus of the protein, which functions in DNA binding and transactivation. This mutation would result in a deletion of 6 amino acid residues at the C terminal of the protein. CONCLUSIONS: The mutation c.797_814del, p.Ser266_Ala271del is a novel mutation in the conserved DNA-binding OAR domain of PITX3 that causes congenital cataract.


Assuntos
Catarata/congênito , Proteínas de Homeodomínio/genética , Análise de Sequência de DNA/métodos , Deleção de Sequência , Fatores de Transcrição/genética , Catarata/genética , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/química , Humanos , Masculino , Herança Paterna , Linhagem , Domínios Proteicos , Fatores de Transcrição/química
19.
Hum Genet ; 138(8-9): 1007-1018, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30919050

RESUMO

Mouse mutants are a long-lasting, valuable tool to identify genes underlying eye diseases, because the absence of eyes, very small eyes and severely affected, cataractous eyes are easily to detect without major technical equipment. In mice, actually 145 genes or loci are known for anophthalmia, 269 for microphthalmia, and 180 for cataracts. Approximately, 25% of the loci are not yet characterized; however, some of the ancient lines are extinct and not available for future research. The phenotypes of the mutants represent a continuous spectrum either in anophthalmia and microphthalmia, or in microphthalmia and cataracts. On the other side, mouse models are still missing for some genes, which have been identified in human families to be causative for anophthalmia, microphthalmia, or cataracts. Finally, the mouse offers the possibility to genetically test the roles of modifiers and the role of SNPs; these aspects open new avenues for ophthalmogenetics in the mouse.


Assuntos
Anoftalmia/genética , Catarata/genética , Olho/fisiopatologia , Microftalmia/genética , Animais , Humanos , Camundongos , Mutação/genética , Fenótipo
20.
Gene ; 692: 113-118, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30659945

RESUMO

The transcription factor v-maf avain musculoaponeurotic fibrosarcoma oncogene homolog (MAF) plays an important role in lens development. It contains a unique extended homology region (EHR) in the DNA binding domain. MAF mutations are associated with phenotypically distinct forms of congenital cataract and show different effects on the transactivation of target genes. Mutations in the MAF EHR region were rarely reported and their corresponding phenotype and impact on target genes' transactivation were not evaluated. A three- generation Chinese family with congenital cataract was recruited. The patients in the family present non-syndromic congenital nuclear and lamellar opacities. A novel MAF mutation (c.812 T > A, p.Val271Glu) was identified by targeted next-generation sequencing. The mutation is in highly conserved EHR region of MAF and co-segregates with the cataract in the family. It is predicted to be pathogenic by multiple algorithms and is absent in a control population. Dual luciferase activity assay shows the mutation significantly impair the transcriptional activity of four crystallin genes (CRYAA, CRYBA4, CRYBA1, and CRYGA) and two non-crystallin genes (HMOX1 and KDELR2). Herein, we report a novel missense mutation in the MAF EHR region of the DNA binding domain in a family with congenital cataract. The mutation is associated with non-syndromic bilateral nuclear cataract and impacts the transactivation of cataract associated genes involved in lens structure and stress response.


Assuntos
Catarata/genética , Cristalinas/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-maf/genética , Sítios de Ligação , Catarata/patologia , Catarata/terapia , Extração de Catarata , Feminino , Heme Oxigenase-1/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Domínios Proteicos , Proteínas Proto-Oncogênicas c-maf/metabolismo , Ativação Transcricional , Proteínas de Transporte Vesicular/genética , Cadeia A de beta-Cristalina/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA