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1.
Int J Biol Macromol ; 172: 475-482, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33454329

RESUMO

Despite of increasingly accumulated genetic variations of autosomal dominant congenital cataracts (ADCC), the causative genes of many ADCC patients remains unknown. In this research, we identified a novel F30S mutation in γS-crystallin from a three-generation Chinese family with ADCC. The patients possessing the F30S mutation exhibited nuclear cataract phenotype. The potential molecular mechanism underlying ADCC by the F30S mutation was investigated by comparing the structural features, stability and aggregatory potency of the mutated protein with the wild type protein. Spectroscopic experiments indicated that the F30S mutation did not affect γS-crystallin secondary structure compositions, but modified the microenvironments around aromatic side-chains. Thermal and chemical denaturation studies indicated that the mutation destabilized the protein and increased its aggregatory potency. The mutation altered the two-state unfolding of γS-crystallin to a three-state unfolding with the accumulation of an unfolding intermediate. The almost identical values in the changes of Gibbs free energies for transitions from the native state to intermediate and from the intermediate to unfolded state suggested that the mutation probably disrupted the cooperativity between the two domains during unfolding. Our results expand the genetic variation map of ADCC and provide novel insights into the molecular mechanism underlying ADCC caused by mutations in ß/γ-crystallins.


Assuntos
Catarata/congênito , Mutação , Estresse Fisiológico/genética , gama-Cristalinas/química , Adolescente , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Catarata/genética , Catarata/patologia , Pré-Escolar , Família , Feminino , Humanos , Cinética , Masculino , Modelos Moleculares , Linhagem , Agregados Proteicos/genética , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Desdobramento de Proteína , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Termodinâmica , gama-Cristalinas/genética , gama-Cristalinas/metabolismo
2.
Medicine (Baltimore) ; 100(2): e22902, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466118

RESUMO

RATIONALE: Warburg Micro syndrome is a rare, autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and genital systems. This case report describes a novel mutation in the RAB3GAP1 gene associated with Warburg Micro syndrome. PATIENT CONCERNS: A 6-month-old female infant with bilateral congenital cataracts and developmental delay was referred to our department for further assessment. She presented with facial dysmorphic features, including a prominent forehead, microphthalmia, wide nasal bridge, relatively narrow mouth, large anteverted ears, and micrognathia. DIAGNOSES: The patient was diagnosed with Warburg Micro syndrome based on clinical manifestations, as well as a novel homozygous mutation in RAB3GAP1: c.75-2A>C. Both parents were identified as heterozygotic carriers of this mutation. INTERVENTIONS: Bilateral cataract extraction and anterior vitrectomy were performed at age 6 months, followed by physical rehabilitation. Convex lenses were used to protect the eyes postoperatively until intraocular lens implantation. OUTCOMES: Although the patient received physical rehabilitation, she suffered global developmental delay. LESSONS: The c.75-2A>C mutation in RAB3GAP1 expands the spectrum of known mutations in this gene, and it may be associated with Warburg Micro syndrome. Genetic counselors may wish to take this finding into consideration, especially given the poor prognosis associated with the disease.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Córnea/anormalidades , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Proteínas rab3 de Ligação ao GTP/genética , Catarata/genética , China , Feminino , Humanos , Lactente
3.
Hum Genet ; 140(4): 649-666, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33389129

RESUMO

Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.


Assuntos
Catarata/genética , Mutação de Sentido Incorreto , Sinais de Orientação para Peroxissomos , Receptor 1 de Sinal de Orientação para Peroxissomos/genética , Peroxissomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico Ativo , Catarata/congênito , Catarata/metabolismo , Cromossomos Humanos Par 12 , Consanguinidade , Feminino , Ligação Genética , Humanos , Cristalino/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor 1 de Sinal de Orientação para Peroxissomos/metabolismo , Proteína Sequestossoma-1/metabolismo , Sequenciamento Completo do Exoma
4.
JAMA Ophthalmol ; 139(2): 165-173, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33331850

RESUMO

Importance: Glaucoma-related adverse events constitute serious complications of cataract removal in infancy, yet long-term data on incidence and visual outcome remain lacking. Objective: To identify and characterize incident cases of glaucoma and glaucoma-related adverse events (glaucoma + glaucoma suspect) among children in the Infant Aphakia Treatment Study (IATS) by the age of 10.5 years and to determine whether these diagnoses are associated with optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) assessment. Design, Setting, and Participants: Analysis of a multicenter randomized clinical trial of 114 infants with unilateral congenital cataract who were aged 1 to 6 months at surgery. Data on long-term glaucoma-related status and outcomes were collected when children were 10.5 years old (July 14, 2015, to July 12, 2019) and analyzed from March 30, 2019, to August 6, 2019. Interventions: Participants were randomized at cataract surgery to either primary intraocular lens (IOL), or aphakia (contact lens [CL]). Standardized definitions of glaucoma and glaucoma suspect were created for IATS and applied for surveillance and diagnosis. Main Outcomes and Measures: Development of glaucoma and glaucoma + glaucoma suspect in operated-on eyes up to age 10.5 years, plus intraocular pressure, axial length, RNFL (by optical coherence tomography), and ONH photographs. Results: In Kaplan-Meier analysis, for all study eyes combined (n = 114), risk of glaucoma after cataract removal rose from 9% (95% CI, 5%-16%) at 1 year, to 17% (95% CI, 11%-25%) at 5 years, to 22% (95% CI, 16%-31%) at 10 years. The risk of glaucoma plus glaucoma suspect diagnosis after cataract removal rose from 12% (95% CI, 7%-20%) at 1 year, to 31% (95% CI, 24%-41%) at 5 years, to 40% (95% CI, 32%-50%) at 10 years. Risk of glaucoma and glaucoma plus glaucoma suspect diagnosis at 10 years was not significantly different between treatment groups. Eyes with glaucoma (compared with eyes with glaucoma suspect or neither) had longer axial length but relatively preserved RNFL and similar ONH appearance and visual acuity at age 10 years. Conclusions and Relevance: Risk of glaucoma-related adverse events continues to increase with longer follow-up of children following unilateral cataract removal in infancy and is not associated with primary IOL implantation. Development of glaucoma (or glaucoma suspect) after removal of unilateral congenital cataract was not associated with worse visual acuity outcomes at 10 years. Trial Registration: ClinicalTrials.gov Identifier: NCT00212134.


Assuntos
Afacia Pós-Catarata/cirurgia , Extração de Catarata/efeitos adversos , Catarata/terapia , Oftalmopatias Hereditárias/cirurgia , Glaucoma/epidemiologia , Implante de Lente Intraocular/efeitos adversos , Lentes Intraoculares/efeitos adversos , Afacia Pós-Catarata/diagnóstico , Afacia Pós-Catarata/epidemiologia , Catarata/congênito , Catarata/diagnóstico , Catarata/epidemiologia , Criança , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/epidemiologia , Feminino , Glaucoma/diagnóstico por imagem , Glaucoma/fisiopatologia , Humanos , Incidência , Lactente , Pressão Intraocular , Masculino , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Acuidade Visual
6.
Medicine (Baltimore) ; 99(39): e22140, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991407

RESUMO

To observe the ocular axis, visual acuity and intraocular pressure (IOP) of aphakic eye in infants with congenital cataract and complex microphthalmos after first-stage cataract surgery.This retrospective study included infants with congenital cataract and operated at the Qingdao Eye Hospital between January 2010 and December 2014. The infants were divided into 2 groups: preoperative axial length <18 mm (microphthalmos) or ≥18 mm (controls). Follow-up lasted 24 months; visual acuity, axial length, and IOP were evaluated.There were 28 infants (55 eyes) in the microphthalmos group and 35 (61 eyes) in the control group. The preoperative visual acuity was negative for optokinetic nystagmus, while the postoperative visual acuity was positive for optokinetic nystagmus in both groups. The growth rate was higher in the microphthalmos group (1.4 ±â€Š0.8 vs 0.8 ±â€Š0.4 mm/yr, P < .001 vs controls). The axial length was smaller in the microphthalmos group at all time points compared with the control group (all P < .001). There was no changes in IOP in the microphthalmos group from baseline to 24 months (P = .147), but the IOP was slightly decreased in the control group (P = .015).Cataract surgery may contribute to ocular axis growth in infants with complex microphthalmos.


Assuntos
Comprimento Axial do Olho/crescimento & desenvolvimento , Extração de Catarata/métodos , Catarata/congênito , Afacia Pós-Catarata/etiologia , Estudos de Casos e Controles , Catarata/complicações , Feminino , Humanos , Lactente , Masculino , Microftalmia/complicações , Estudos Retrospectivos , Acuidade Visual
7.
Cytogenet Genome Res ; 160(6): 309-315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599602

RESUMO

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Homozigoto , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Dissomia Uniparental/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Catarata/genética , Feminino , Humanos , Lactente , Perda de Heterozigosidade/genética , Masculino , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas rab3 de Ligação ao GTP/genética
8.
Zhonghua Yan Ke Za Zhi ; 56(5): 386-392, 2020 May 11.
Artigo em Chinês | MEDLINE | ID: mdl-32450672

RESUMO

Congenital cataract is a common eye disease that seriously affects the visual development of infants and children. Nearly 30% of cases have cataract-linked, inherited mutations. With the development of molecular genetics, especially gentechnik, more and more genes, such as crystallin genes, membrane protein genes, transcription factors and cytoskeletal protein genes, have been confirmed to be associated with the onset of congenital cataract. There have been many studies on crystallin genes, but studies on the pathogenesis of membrane protein genes have gradually been emphasized as well in recent years. Furthermore, major intrinsic protein (MIP) genes belong to membrane protein genes, and the MIP translated by them accounts for about 50% of the total cell membrane proteins.It has been found that more than twenty mutations in MIP genes participate in the development of congenital cataract. How do these mutations further affect the cellular function and eventually lead to cataract? The recent progression about inherited congenital cataract related with MIP genes at the levels of genes and proteins is summarized in this review. (Chin J Ophthalmol, 2020, 56: 386-392).


Assuntos
Catarata , Cristalinas , Mutação , Catarata/congênito , Catarata/genética , Criança , Humanos
9.
Am J Ophthalmol ; 216: 147-155, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32304705

RESUMO

PURPOSE: To report the change in globe axial length (AL) from the time of unilateral cataract surgery at age 1-7 months to age 10.5 years for infants enrolled in the Infant Aphakia Treatment Study, and to compare AL growth of operated eyes with that of fellow unoperated eyes. DESIGN: Comparative case series. METHODS: AL growth was analyzed relative to treated vs fellow eye, contact lens (CL) vs intraocular lens (IOL), visual acuity (VA) outcome, and the need for surgery for visual axis opacification. Eyes with glaucoma or glaucoma suspect were excluded from the primary analysis but reported separately. RESULTS: Fifty-seven patients have reliable AL data available at both visits. AL was shorter in treated eyes preoperatively (P < .0001) and at 10.5 years of age (P = .021) but AL growth was not different (4.7 mm, P = .99). The growth (70.2% up to age 5 and 29.8% from age 5 to 10.5) was similar in the CL and the IOL group (P = .79). Eyes grew 4.4 mm when visual acuity (VA) was better than 20/200, and 5.2 mm when VA was 20/200 or worse (P = .076). Eyes receiving additional surgery grew more than eyes not receiving additional surgery (P = .052). Patients with glaucoma showed significantly more eye growth (7.3 mm) than those without glaucoma (4.7 mm) and glaucoma suspects (5.1 mm) (P < .05). CONCLUSIONS: Eyes with glaucoma or poor VA often grew longer than the fellow eye. Overall, treated eyes grew similarly in the IOL and CL groups and also kept pace with the growth of the fellow eyes.


Assuntos
Afacia Pós-Catarata/terapia , Comprimento Axial do Olho/crescimento & desenvolvimento , Catarata/congênito , Lentes de Contato , Implante de Lente Intraocular , Afacia Pós-Catarata/etiologia , Extração de Catarata , Criança , Feminino , Seguimentos , Glaucoma/complicações , Humanos , Lactente , Masculino , Órbita , Acuidade Visual/fisiologia
10.
Eur J Ophthalmol ; 30(5): 966-973, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32340490

RESUMO

BACKGROUND: Lowe syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the oculocerebral renal syndrome of Lowe (OCRL) gene are found in Lowe syndrome patients. Although loss of vision is a major concern for families and physicians who take care of Lowe syndrome children, definitive cause of visual loss is still unclear. Children usually present with bilateral dense cataracts at birth and glaucoma, which occurs in more than half of cases, either concurrently or following cataract surgery. MATERIALS AND METHODS: A retrospective review was conducted on the prevalence and characteristics of ocular findings among families of patients with Lowe syndrome with 137 uniquely affected individuals. RESULTS: Of 137 patients, all had bilateral congenital cataracts. Nystagmus was reported in 69.3% of cases, glaucoma in 54.7%, strabismus in 35.0%, and corneal scar in 18.2% of patients. Glaucoma was reported as the most common cause of blindness (46%) followed by corneal scars (41%). Glaucoma occurred in 54.7% of patients and affected both eyes in the majority of cases. Of these patients, 55% underwent surgery for glaucoma, while the remaining patients used medications to control their eye pressure. Timolol and latanoprost were the most commonly used medications. Although trabeculectomy and goniotomy are commonly used for pressure management, aqueous tube shunts had the best outcomes. CONCLUSION: Ocular manifestations in individuals with Lowe syndrome and carriers with OCRL mutation are reported which may help familiarize clinicians with the ocular manifestations and management of a rare and complex syndrome.


Assuntos
Oftalmopatias/epidemiologia , Síndrome Oculocerebrorrenal/epidemiologia , Catarata/congênito , Catarata/diagnóstico , Catarata/epidemiologia , Extração de Catarata , Criança , Pré-Escolar , Doenças da Córnea/diagnóstico , Doenças da Córnea/epidemiologia , Oftalmopatias/diagnóstico , Feminino , Glaucoma/diagnóstico , Glaucoma/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Nistagmo Patológico/diagnóstico , Nistagmo Patológico/epidemiologia , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Prevalência , Estudos Retrospectivos , Estrabismo/diagnóstico , Estrabismo/epidemiologia
11.
BMC Mol Cell Biol ; 21(1): 12, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143568

RESUMO

BACKGROUND: Gap junction protein alpha 3 (GJA3), an important pathogenic gene of congenital cataracts, encodes the transmembrane protein connexin46, which functions as an intercellular channel for voltage and chemical gating by forming dodecamers. This study systematically collected nsSNP information for the GJA3 gene from SNP databases and literature and screened for nsSNPs with high risks of pathogenicity. RESULTS: A total of 379 nsSNPs of GJA3 were identified. A total of 88 high-risk pathogenic GJA3 nsSNPs were found, including 31 published nsSNPs associated with congenital cataracts and 57 novel nsSNPs predicted by all eight online tools. The 88 high-risk pathogenic mutations, which are related to 67 amino acids in the wild-type sequences, cause a decrease in protein stability according to I-Mutant 3.0, MUpro and INPS. G2 and R33 were predicted to participate in post-translational modification and ligand binding by ModPred, RaptorX Binding and COACH. Additionally, high-risk mutations were likely to involve highly conserved sites, random coils, alpha helixes, and extracellular loops and were accompanied by changes in amino acid size, charge, hydrophobicity and spatial structure. CONCLUSIONS: Eighty-eight high-risk pathogenic nsSNPs of GJA3 were screened out in the study, 57 of which were newly reported. The combination of multiple in silico tools is highly efficient for targeting pathogenic sites.


Assuntos
Catarata/genética , Conexinas/genética , Polimorfismo de Nucleotídeo Único , Catarata/congênito , Biologia Computacional , Simulação por Computador , Conexinas/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Mutação , Filogenia , Conformação Proteica em alfa-Hélice/genética , Conformação Proteica em Folha beta/genética , Fatores de Risco
12.
Invest Ophthalmol Vis Sci ; 61(3): 25, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32182330

RESUMO

Purpose: To investigate the underlying mechanisms for how the mouse Cx50-R205G point mutation, a homologue of the human Cx50-R198W mutation that is linked to cataract-microcornea syndrome, affects proper lens growth and fiber cell differentiation to lead to severe lens phenotypes. Methods: EdU labeling, immunostaining, confocal imaging analysis, and primary lens epithelial cell culture were performed to characterize the lens epithelial cell (LEC) proliferation and fiber cell differentiation in wild-type and Cx50-R205G mutant lenses in vivo and in vitro. Results: The Cx50-R205G mutation severely disrupts the lens size and transparency. Heterozygous and homozygous Cx50-R205G mutant and Cx50 knockout lenses all show decreased central epithelium proliferation while only the homozygous Cx50-R205G mutant lenses display obviously decreased proliferating LECs in the germinative zone of neonatal lenses. Cultured Cx50-R205G lens epithelial cells reveal predominantly reduced Cx50 gap junction staining but no change of the endoplasmic reticulum stress marker BiP. The heterozygous Cx50-R205G lens fibers show moderately disrupted Cx50 and Cx46 gap junctions while the homozygous Cx50-R205G lens fibers have drastically reduced Cx50 and Cx46 gap junctions with severely altered fiber cell shape in vivo. Conclusions: The Cx50-R205G mutation inhibits both central and equatorial lens epithelial cell proliferation to cause small lenses. This mutation also disrupts the assembly and functions of both Cx50 and Cx46 gap junctions in lens fibers to alter fiber cell differentiation and shape to lead to severe lens phenotypes.


Assuntos
Catarata/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Conexinas/genética , Doenças da Córnea/genética , Células Epiteliais/patologia , Cristalino/patologia , Mutação Puntual , Animais , Animais Recém-Nascidos , Catarata/congênito , Catarata/patologia , Células Cultivadas , Doenças da Córnea/patologia , Técnica Indireta de Fluorescência para Anticorpo , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia de Fluorescência
13.
JAMA Ophthalmol ; 138(4): 365-372, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32077909

RESUMO

Importance: Although intraocular lenses (IOLs) are often implanted in children, little is known whether primary IOL implantation or aphakia and contact lens correction results in better long-term visual outcomes after unilateral cataract surgery during infancy. Objective: To compare long-term visual outcomes with contact lens vs IOL correction following unilateral cataract surgery during infancy. Design, Setting, and Participants: This multicenter randomized clinical trial enrolled 114 infants with a unilateral congenital cataract who underwent cataract surgery with or without primary IOL implantation between 1 and 6 months of age. Data on long-term visual outcomes were collected when the children were age 10.5 years (July 14, 2015, to July 12, 2019) and analyzed from March 30 through August 6, 2019. Interventions: Intraocular lens implantation at the time of cataract surgery. Main Outcomes and Measures: Best-corrected visual acuity using the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) testing protocol. Analysis was performed on an intention-to-treat basis. Results: Best-corrected visual acuity was measured at age 10.5 years for 110 of the 114 patients (96%) enrolled as infants. The participants included 58 girls (53%) and 52 boys (47%). Overall, 27 of the children (25%) had good (logMAR 0.30 [Snellen equivalent, 20/40] or better) visual acuity in the treated eye (12 [22%] in the IOL group and 15 [27%] in the aphakia group), but 50 children (44%) had a visual acuity of logMAR 1.00 (Snellen equivalent, 20/200) or worse (25 [44%] in the IOL group and 25 [44%] in the aphakia group). The median logMAR acuity in the treated eye was similar in children randomized to receive an IOL at the time of cataract extraction (0.89; interquartile range [IQR], 0.33-1.43 [Snellen equivalent, 20/159]) and those who remained aphakic (0.86; IQR, 0.30-1.46 [Snellen equivalent, 20/145]) (IQR, 0.30-1.46; P = .82). Although the overall difference in median visual acuity between the 2 groups was small, the estimate was imprecise (99% CI for the difference in medians was -0.54 to 0.47). Conclusions and Relevance: As in previous phases of the study, visual acuity outcomes were highly variable with only 27 children (25%) achieving excellent visual acuity in their treated eye and 50 children (44%) having poor vision in the treated eye. Implanting an IOL at the time of cataract extraction was neither beneficial nor detrimental to the visual outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT00212134.


Assuntos
Afacia Pós-Catarata/fisiopatologia , Extração de Catarata , Lentes de Contato Hidrofílicas , Lentes Intraoculares , Pseudofacia/fisiopatologia , Acuidade Visual/fisiologia , Catarata/congênito , Criança , Feminino , Seguimentos , Humanos , Lactente , Implante de Lente Intraocular , Masculino , Visão Binocular/fisiologia
14.
PLoS Genet ; 16(2): e1008628, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32101538

RESUMO

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.


Assuntos
Catarata/genética , Epiderme/patologia , Hipotricose/genética , Transferases Intramoleculares/genética , Cristalino/patologia , Adolescente , Animais , Catarata/congênito , Catarata/patologia , Colesterol/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Epiderme/enzimologia , Saúde Holística , Humanos , Hipotricose/congênito , Hipotricose/patologia , Transferases Intramoleculares/metabolismo , Lanosterol/análise , Lanosterol/metabolismo , Cristalino/enzimologia , Masculino , Camundongos , Camundongos Knockout , Mutação , Linhagem , Sebo/química , Sequenciamento Completo do Exoma
15.
Yi Chuan ; 42(2): 161-171, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32102773

RESUMO

Congenital cataract (CC) is a rare disease with dysplasia of the lens, mainly characterized by partial or complete opacity of the lens. The molecular basis of the disease is complex, mutations in over 266 genes associated with congenital cataracts had been reported. In this study, a novel congenital cataract candidate gene TSR1 was identified by whole genome sequencing and Sanger sequencing in a Chinese congenital cataract family. The TSR1 c.202-1G>A substitution affected splicing of TSR1 mRNA was confirmed by a minigene assay. The expression of TSR1 in mouse lens, anterior lens capsule of age-related cataract patients and 24-week human fetal lens were determined by RT-PCR, Western blotting, and immunofluorescence assays. The expression of TSR1 in the embryonic and different developmental stages of the mouse lens was confirmed by analyzing the iSyTE database. The expression of TSR1 was down-regulated in the lens-specific CBP:p300 double knockout mouse, and a set of genes with the same expression pattern of Tsr1 in the CBP:p300 double knockout mouse lens were extracted for protein-protein interaction network analysis, and six proteins were screened for direct interaction with Tsr1. GO function analysis indicated that Tsr1 might play a role in the MAPK-Erk signaling pathway in addition to its involvement in ribosome assembly. This study provided valuable research clues to further clarify the function of Tsr1 in the lens.


Assuntos
Catarata/genética , Cristalino/patologia , Proteínas Ribossômicas/genética , Animais , Grupo com Ancestrais do Continente Asiático , Catarata/congênito , China , Humanos , Camundongos , Camundongos Knockout , Mutação , Linhagem , RNA Mensageiro
16.
EBioMedicine ; 51: 102621, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901869

RESUMO

BACKGROUND: Approximately 1 in 33 newborns is affected by congenital anomalies worldwide. We aimed to develop a practical model for identifying infants with a high risk of congenital cataracts (CCs), which is the leading cause of avoidable childhood blindness. METHODS: This case-control study was performed in the Zhongshan Ophthalmic Center and involved 2005 subjects, including 1274 children with CCs and 731 healthy controls. The CC identification models were established based on birth conditions, family medical history, and family environmental factors using the random forest (RF) and adaptive boosting methods (trained by 1129 CC cases and 609 healthy controls), which were tested by internal 4-fold cross-validation and external validation (145 CC cases and 122 healthy controls). The models were also tested using 4 datasets with gradually reduced proportions of CC patients (bilateral cases) to validate their performance in an approximate simulation of a clinical environment with a relatively low disease prevalence. FINDINGS: The CC identification models showed high discrimination in both the 4-fold cross validation (area under the curve (AUC)=0.91 [95% confidence interval: 0.88-0.94] in bilateral cases; 0.82 [0.77-0.89] in unilateral cases) and external validation (AUC=0.93±0.05 in bilateral cases; 0.86±0.01 in unilateral cases), and achieved stable performance in the clinical tests (AUC=0.94-0.96 in the four subgroups by RF). Furthermore, family history of CC, low parental education level, and comorbidity were identified as the top three most relevant factors to both bilateral and unilateral CC diagnosis. INTERPRETATION: Our CC identification models can accurately discriminate CC patients from healthy children and have the potential to serve as a complementary screening procedure, especially in undeveloped and remote areas.


Assuntos
Catarata/congênito , Catarata/diagnóstico , Aprendizado de Máquina , Modelos Biológicos , Algoritmos , Área Sob a Curva , Estudos de Casos e Controles , Catarata/genética , Pré-Escolar , Feminino , Humanos , Padrões de Herança/genética , Masculino , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco
17.
PLoS One ; 15(1): e0227859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935276

RESUMO

In order to provide a cost-effective method to narrow down the number of pathogenic Crystallin beta A4 (CRYBA4) non-synonymous single nucleotide polymorphisms (nsSNPs), we collected nsSNP information of the CRYBA4 gene from SNP databases and literature, predicting the pathogenicity and possible changes of protein properties and structures using multiple bioinformatics tools. The nsSNP data of the CRYBA4 gene were collected from 4 databases and published literature. According to 12 criteria, six bioinformatics tools were chosen to predict the pathogenicity. I-Mutant 2.0, Mupro and INPS online tools were used to analyze the effects of amino acid substitution on protein stability by calculating the value of ΔΔG. ConSurf, SOPMA, GETAREA and HOPE online tools were used to predict the evolutionary conservation of amino acids, solvent accessible surface areas, and the physical and chemical properties and changes of protein structure. All 157 CRYBA4 nsSNPs were analyzed. Forty-four CRYBA4 high-risk pathogenic nsSNPs (predicted to be pathogenic by all six software tools) were detected out of the 157 CRYBA4 nsSNPs, four of which (c.283C>T, p.R95W; c.449T>A, p.V150D; c.475G>A, p.G159R; c.575G>C, p.R192P) should be focused on because of their high potential pathogenicity and possibility of changing protein properties. Thirty high-risk nsSNPs were predicted to cause a decrease of protein stability. Twenty-nine high-risk nsSNPs occurred in evolutionary conserved positions. Twenty-two high-risk nsSNPs occurred in the core of the protein. It is predicted that these high-risk pathogenic nsSNPs can cause changes in the physical and chemical properties of amino acids, resulting in structural changes of proteins and changes in the interactions between domains and other molecules, thus affecting the function of proteins. This study provides important reference value when narrowing down the number of pathogenic CRYBA4 nsSNPs and studying the pathogenesis of congenital cataracts. By using this method, we can easily find 44 high-risk pathogenic nsSNPs out of 157 CRYBA4 nsSNPs.


Assuntos
Catarata/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Cadeia A de beta-Cristalina/genética , Substituição de Aminoácidos/genética , Catarata/congênito , Catarata/patologia , Biologia Computacional , Simulação por Computador , Estudos de Associação Genética , Humanos , Mutação , Fenótipo , Conformação Proteica , Estabilidade Proteica , Software , Cadeia A de beta-Cristalina/química
19.
Ophthalmology ; 127(4): 501-510, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987642

RESUMO

PURPOSE: To evaluate outcomes of bilateral cataract surgery in infants 1 to 7 months of age performed by Infant Aphakia Treatment Study (IATS) investigators during IATS recruitment and to compare them with IATS unilateral outcomes. DESIGN: Retrospective case series review at 10 IATS sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study (TAPS) is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent bilateral cataract surgery with or without intraocular lens (IOL) placement during IATS enrollment years 2004 through 2010. MAIN OUTCOME MEASURES: Visual acuity (VA), strabismus, adverse events (AEs), and reoperations. RESULTS: One hundred seventy-eight eyes (96 children) were identified with a median age of 2.5 months (range, 1-7 months) at the time of cataract surgery. Forty-two eyes (24%) received primary IOL implantation. Median VA of the better-seeing eye at final study visit closest to 5 years of age with optotype VA testing was 0.35 logarithm of the minimum angle of resolution (logMAR; optotype equivalent, 20/45; range, 0.00-1.18 logMAR) in both aphakic and pseudophakic children. Corrected VA was excellent (<20/40) in 29% of better-seeing eyes, 15% of worse-seeing eyes. One percent showed poor acuity (≥20/200) in the better-seeing eye, 12% in the worse-seeing eye. Younger age at surgery and smaller (<9.5 mm) corneal diameter at surgery conferred an increased risk for glaucoma or glaucoma suspect designation (younger age: odds ratio [OR], 1.44; P = 0.037; and smaller cornea: OR, 3.95; P = 0.045). Adverse events also were associated with these 2 variables on multivariate analysis (younger age: OR, 1.36; P = 0.023; and smaller cornea: OR, 4.78; P = 0.057). Visual axis opacification was more common in pseudophakic (32%) than aphakic (8%) eyes (P = 0.009). Unplanned intraocular reoperation occurred in 28% of first enrolled eyes (including glaucoma surgery in 10%). CONCLUSIONS: Visual acuity after bilateral cataract surgery in infants younger than 7 months is good, despite frequent systemic and ocular comorbidities. Although aphakia management did not affect VA outcome or AE incidence, IOL placement increased the risk of visual axis opacification. Adverse events and glaucoma correlated with a younger age at surgery and glaucoma correlated with the presence of microcornea.


Assuntos
Afacia Pós-Catarata/fisiopatologia , Extração de Catarata , Pseudofacia/fisiopatologia , Estrabismo/fisiopatologia , Acuidade Visual/fisiologia , Catarata/congênito , Feminino , Seguimentos , Humanos , Lactente , Implante de Lente Intraocular , Masculino , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Testes Visuais
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