Uma catarata que tem sua causa em uma mutação genética em apenas uma das cópias do gene CRYGC, localizado no cromossomo 2q33.
Introdução
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Uma catarata que tem sua causa em uma mutação genética em apenas uma das cópias do gene CRYGC, localizado no cromossomo 2q33.
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
9 genes identificados com associação a esta condição.
Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells. Vimentin is attached to the nucleus, endoplasmic reticulum, and mitochondria, either laterally or terminally. Plays a role in cell directional movement, orientation, cell sheet organization and Golgi complex polarization at the cell migration front (By similarity). Protects SCRIB from proteasomal degradation and facilitates its localization to intermediate filaments in a cell conta
CytoplasmCytoplasm, cytoskeletonNucleus matrixCell membraneCell projection, axon
Cataract 30, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function.
Acts as a transcriptional activator or repressor. Involved in embryonic lens fiber cell development. Recruits the transcriptional coactivators CREBBP and/or EP300 to crystallin promoters leading to up-regulation of crystallin gene during lens fiber cell differentiation. Activates the expression of IL4 in T helper 2 (Th2) cells. Increases T-cell susceptibility to apoptosis by interacting with MYB and decreasing BCL2 expression. Together with PAX6, transactivates strongly the glucagon gene promote
Nucleus
Crystallins are the dominant structural components of the vertebrate eye lens
Cataract 2, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT2 includes Coppock-like cataract, among others. Coppock-like cataract is a congenital pulverulent disk-like opacity involving the embryonic nucleus with many tiny white dots in the lamellar portion of the lens. It is usually bilateral and dominantly inherited. In some cases, CTRCT2 is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye.
Structural component of eye lens gap junctions (PubMed:18006672, PubMed:19756179). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane (By similarity). Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:18006672, PubMed:19756179)
Cell membraneCell junction, gap junction
Cataract 1, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT1 includes congenital, zonular pulverulent, nuclear progressive, nuclear pulverulent, nuclear total, total, and posterior subcapsular types of cataract. Zonular or lamellar cataracts are opacities, broad or narrow, usually consisting of powdery white dots affecting only certain layers or zones between the cortex and nucleus of an otherwise clear lens. The opacity may be so dense as to render the entire central region of the lens completely opaque, or so translucent that vision is hardly if at all impeded. Zonular cataracts generally do not involve the embryonic nucleus, though sometimes they involve the fetal nucleus. Usually sharply separated from a clear cortex outside them, they may have projections from their outer edges known as riders or spokes. In some cases cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye.
Crystallins are the dominant structural components of the vertebrate eye lens
Cataract 4, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT4 includes crystalline aculeiform, congenital cerulean and non-nuclear polymorphic cataracts, among others. Crystalline aculeiform cataract is characterized by fiberglass-like or needle-like crystals projecting in different directions, through or close to the axial region of the lens. Non-nuclear polymorphic cataract is a partial opacity with variable location between the fetal nucleus of the lens and the equator. The fetal nucleus is normal. The opacities are irregular and look similar to a bunch of grapes and may be present simultaneously in different lens layers. Congenital cerulean cataract is characterized by peripheral bluish and white opacifications organized in concentric layers with occasional central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. Involvement is usually bilateral. Visual acuity is only mildly reduced in childhood. In adulthood, the opacifications may progress, making lens extraction necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Although the lesions may take on various colors, a dull blue is the most common appearance and is responsible for the designation cerulean cataract.
Crystallins are the dominant structural components of the vertebrate eye lens
Cataract 17, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. CTRCT17 includes nuclear and pulverulent cataracts, among others. Nuclear cataracts affect the central nucleus of the eye, are often not highly visually significant. The density of the opacities varies greatly from fine dots to a dense, white and chalk-like, central cataract. The condition is usually bilateral. Nuclear cataracts are often combined with opacified cortical fibers encircling the nuclear opacity, which are referred to as cortical riders. Pulverulent cataracts are characterized by a dust-like, 'pulverised' appearance of the opacities which can be found in any part of the lens.
Crystallins are the dominant structural components of the vertebrate eye lens
Cataract 3, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT3 includes congenital cerulean and sutural cataract with punctate and cerulean opacities, among others. Cerulean cataract is characterized by peripheral bluish and white opacifications organized in concentric layers with occasional central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. Involvement is usually bilateral. Visual acuity is only mildly reduced in childhood. In adulthood, the opacifications may progress, making lens extraction necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Although the lesions may take on various colors, a dull blue is the most common appearance and is responsible for the designation cerulean cataract. Sutural cataract with punctate and cerulean opacities is characterized by white opacification around the anterior and posterior Y sutures, and grayish and bluish, spindle shaped, oval punctate and cerulean opacities of various sizes arranged in lamellar form. The spots are more concentrated towards the peripheral layers and do not delineate the embryonal or fetal nucleus. Phenotypic variation with respect to the size and density of the sutural opacities as well as the number and position of punctate and cerulean spots is observed among affected subjects.
Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA (PubMed:28935373). Plays a role in maintenance of retinal lens optical clarity (By similarity)
Cell membraneCytoplasmCytoplasm, cytoskeletonCytoplasm, cell cortex
Cataract 12, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. The opacities can be nuclear, sutural, stellate cortical, lamellar, cortical, nuclear embryonic, Y-sutural, punctate cortical, congenital or with juvenile- and adult-onset.
Structural component of lens fiber gap junctions (PubMed:30044662). Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells (By similarity). They are formed by the docking of two hexameric hemichannels, one from each cell membrane. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore (PubMed:30044662)
Cell membraneCell junction, gap junction
Cataract 14, multiple types
An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT14 includes zonular pulverulent cataract, among others. Zonular or lamellar cataracts are opacities, broad or narrow, usually consisting of powdery white dots affecting only certain layers or zones between the cortex and nucleus of an otherwise clear lens. The opacity may be so dense as to render the entire central region of the lens completely opaque, or so translucent that vision is hardly if at all impeded. Usually sharply separated from a clear cortex outside them, they may have projections from their outer edges known as riders or spokes.
Variantes genéticas (ClinVar)
215 variantes patogênicas registradas no ClinVar.
Classificação de variantes (ClinVar)
Distribuição de 51 variantes classificadas pelo ClinVar.
Vias biológicas (Reactome)
12 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
Tratamento e manejo
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Pesquisa ativa
Ensaios clínicos abertos e novidades científicas recentes
Pesquisa e ensaios clínicos
Nenhum ensaio clínico registrado para esta condição.
Publicações mais relevantes
Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India.
To identify the underlying genetic defects in autosomal dominant (ADCC) and autosomal recessive (ARCC) congenital cataract families from North India. Detailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed using Sanger sequencing in the known candidate genes for crystallins, connexins, and membrane proteins. The pathogenicity of identified variants was assessed bioinformatically. In two ADCC families (CC-281 and CC-3015) with posterior lenticonus cataract, a novel change c.263C > T (p.P88L) in GJA3 in CC-281 family and a previously reported substitution c.388C > T (p.R130C) in LIM2 in CC-3015 family was observed. In an ARCC family (CC-3005) having central pulverulent cataract, a novel frameshift deletion (c.764delT;p.L255R46fs) in GJA3 was detected. The observed variants segregated completely with phenotypes in the affected members and were neither present in unaffected family members nor in the ethnically matched 150 controls (tested for two novel variants), hence excluding these as polymorphisms. Present study identified two novel mutations i.e., c.263C > T;p.P88L and c.764delT;p.L255R46fs in GJA3 in an ADCC and an ARCC family having posterior lenticonus and central pulverulent cataract, respectively. In another ADCC family with posterior lenticonus cataract, a previously reported mutation c.388C > T;p.R130C in LIM2 was observed. R130 may be a mutation hotspot as previously ADCC families from different ethnicities (UK/Czechia, China, Spain, Japan) also harbored the same substitution, however, with different phenotypes i.e., nuclear pulverulent, membranous, nuclear, lamellar, and sutural/lamellar. Findings in present study thus expand the mutation spectrum and phenotypic heterogeneity linked with GJA3 and LIM2.
Analysis of the dominant mutation N188T of human connexin46 (hCx46) using concatenation and molecular dynamics simulation.
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.
Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.
Congenital cataract, opacification of the ocular lens, is clinically and genetically a heterogeneous childhood disease. In this study we aimed to identify the underlying genetic cause of isolated autosomal-dominant lamellar cataract in a multi-generation English family. Whole-genome sequencing (WGS) was undertaken in two affected subjects and one unaffected individual. Segregation analysis was performed and a known cataract-causing mutation was identified. Segregation was further validated by sanger sequencing in the entire pedigree. A heterozygous mutation c.7 G > T; p.D3Y was identified in an NH2-terminal region of the gap junction protein GJA3 and found to co-segregate with disease. We have identified a recurrent mutation in GJA3 in a large British pedigree causing the novel phenotype of autosomal-dominant congenital lamellar cataract. Previously, p.D3Y was found in a Hispanic family causing pulverulent cataract. WGS proved an efficient method to find the underlying molecular cause in this large family, which could not be mapped due to uninformative markers.
Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract.
Congenital cataracts are one of the common eye disorders leading to visual impairment or blindness in children worldwide. We found a Chinese family with autosomal dominant pulverulent cataract. To identify the pathogenic gene mutation in a Chinese family with autosomal dominant inherited pulverulent cataract. After obtained informed consent, detailed ophthalmic examinations were carried out; genomic DNAs were obtained from seven family members in a three-generation Chinese family with three affected. All exons of candidate genes were amplified by polymerase chain reaction and were sequenced performed by bidirectional sequencing. By sequencing the encoding regions of the candidate genes, a missense mutation (c. 176C>T) was detected in gap junction protein alpha 3 genes (GJA3), which resulted in the substitution of highly conserved proline by leucine at codon 59 (p.P59L). The mutation co-segregated with all patients and was absent in 100 normal Chinese controls. The study identified a missense mutation (c. 176C>T) in GJA3 gene associated with autosomal dominant congenital pulverulent cataract in a Chinese family. It gave further evidence of phenotype heterogeneity for P59L mutation in GJA3 associated with congenital cataract.
Whole Exome Sequencing Reveals a Mutation in CRYBB2 in a Large Mexican Family with Autosomal Dominant Pulverulent Cataract.
Congenital cataract, an important cause of reversible blindness, is due to several causes including Mendelian inheritance. Thirty percent of cataracts are hereditary with participation of the gamma crystallin genes. Clinical and genetic heterogeneity is observed in patients with gene mutations and congenital cataract; about 40 genetic loci have been associated with hereditary cataract. In this study, we identified the underlying genetic cause of an autosomal dominant pulverulent cataract (ADPC) in a large Mexican family. Twenty-one affected patients and 20 healthy members of a family with ADPC were included. Genomic DNA was analyzed by whole exome sequencing in the proband, a normal daughter, and in an affected son, whereas DNA Sanger sequencing was performed in all members of the family. After the bioinformatics analysis, all samples were genotyped using Sanger sequencing to eliminate variants that do not cosegregate with the cataract. We observed a perfect cosegregation of a nonsense mutation c.475C>T (p.Q155*) in exon 6 of the CRYBB2 gene with ADPC. We calculated a logarithm of the odds score of 5.5. This mutation was not detected in healthy members of the family and in 100 normal controls. This is the first Mexican family with ADPC associated with a p.Q155* mutation. Interestingly, this specific mutation in the CRYBB2 gene seems to be exclusively associated with pulverulent/cerulean cataract (with some clinical variability) independent of the population's genetic background.
Publicações recentes
Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India.
Analysis of the dominant mutation N188T of human connexin46 (hCx46) using concatenation and molecular dynamics simulation.
Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.
Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract.
Whole Exome Sequencing Reveals a Mutation in CRYBB2 in a Large Mexican Family with Autosomal Dominant Pulverulent Cataract.
📚 EuropePMC20 artigos no totalmostrando 7
Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India.
BMC genomicsAnalysis of the dominant mutation N188T of human connexin46 (hCx46) using concatenation and molecular dynamics simulation.
FEBS open bioWhole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.
Eye (London, England)Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract.
Indian journal of ophthalmologyWhole Exome Sequencing Reveals a Mutation in CRYBB2 in a Large Mexican Family with Autosomal Dominant Pulverulent Cataract.
Molecular syndromologyPhenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis).
Transactions of the American Ophthalmological SocietyThe cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels.
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India.
- Analysis of the dominant mutation N188T of human connexin46 (hCx46) using concatenation and molecular dynamics simulation.
- Whole-genome sequencing reveals a recurrent missense mutation in the Connexin 46 (GJA3) gene causing autosomal-dominant lamellar cataract.
- Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract.
- Whole Exome Sequencing Reveals a Mutation in CRYBB2 in a Large Mexican Family with Autosomal Dominant Pulverulent Cataract.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:98984(Orphanet)
- MONDO:0011430(MONDO)
- GARD:16884(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Q27674889(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar