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Frontiers in Genetics 2022is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However,...
is a nuclear transcription factor gene that is highly conserved among species. Variants within could result in optic nerve colobomas and kidney hypoplasia. However, little clinical and genetic information is currently available about variants in Chinese children. This study aims to further understand the clinical manifestations and genetic characteristics of variants in Chinese population. In this single-center retrospective study, we analyzed the clinical data of 10 children identified as carriers of variants by gene sequencing. All the variants found in this study were analyzed using prediction and American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The mean age for developing the first symptom in 10 unrelated children was 7.2 years old. Proteinuria and bilateral kidney dysplasia were found in every patient. Two children underwent kidney histological examination; one child showed high-intensity C1q deposition in the kidney, and the other child showed focal segmental glomerular sclerosis (FSGS). Three children had -related ocular abnormalities, including nystagmus, retinal exudation, amblyopia, microphthalmia, microcornea, and total blindness. In addition, one patient had the comorbidity of oculocutaneous albinism (OCA). Eight different variants were found in ten patients, three of which were reported for the first time. We reported some patients with unique manifestations and comorbidities, and we reported three variants that have not been previously identified. The gene is prone to spontaneous variants, and the outcome of patients is unfavorable. Because of the lack of specific therapy, genetic testing should be recommended for individuals with obvious evidence of kidney dysplasia and eye abnormalities, and kidney protective treatment should be initiated early.
PubMed: 35444690
DOI: 10.3389/fgene.2022.799562 -
Molecular Vision 2009To report the identification of a novel nonsense mutation in CRYGC in a Chinese family with autosomal dominant congenital nuclear cataracts and microcornea.
PURPOSE
To report the identification of a novel nonsense mutation in CRYGC in a Chinese family with autosomal dominant congenital nuclear cataracts and microcornea.
METHODS
We investigated a four-generation Chinese family with six members affected with nuclear cataracts and microcornea. The family resides in a relatively isolated region of northern China. Genomic DNA was isolated from blood leucocytes, genotyping was performed using more than 100 microsatellite markers for the known cataract candidate gene loci, and LOD scores were calculated using the LINKAGE programs. Mutations were detected by DNA sequence analysis of the candidate genes.
RESULTS
Evidence for linkage was detected at marker D2S325 (LOD score [Z]=2.29, recombination fraction [theta]=0.0), which closely flanks the gamma-crystallin gene cluster (CRYGA-CRYGD) on chromosome 2q32.3-q35. Direct sequencing of the candidate CRYGA-CRYGD gene cluster revealed a c.470G>A transversion in exon 3 of CRYGC, which cosegregated with cataracts in the family and was not observed in 100 normal controls. This single nucleotide change was predicted to introduce a translation stop codon at tryptophan 157 (W157X).
CONCLUSIONS
The present study has identified a novel nonsense mutation in CRYGC associated with autosomal dominant cataracts and microcornea in a Chinese family. Our finding expands the spectrum of CRYGC mutations associated with congenital cataract and confirms the role of gamma-crystallin in the pathogenesis of congenital nuclear cataracts.
Topics: Cataract; China; Codon, Nonsense; Cornea; DNA Mutational Analysis; Family; Female; Genes, Dominant; Genetic Linkage; Humans; Lod Score; Male; Microsatellite Repeats; Pedigree; Polymorphism, Single Nucleotide; gamma-Crystallins
PubMed: 19204787
DOI: No ID Found -
American Journal of Human Genetics Aug 2019While genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using...
While genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using exome-sequencing analysis and review of matchmaker databases, we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37-p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile-in unrelated individuals with a previously unrecognized syndrome. Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual. WDR37 encodes a protein of unknown function with seven predicted WD40 domains and no previously reported human pathogenic variants. Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization. CRISPR-Cas9-mediated genome editing generated zebrafish mutants with novel missense and frameshift alleles: p.Ser129Phe, p.Ser129Cys (which replicates one of the human variants), p.Ser129Tyr, p.Lys127Cysfs, and p.Gln95Argfs. Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood, suggesting a potential dominant-negative mechanism for the missense variants. RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways. This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions.
Topics: Abnormalities, Multiple; Adult; Amino Acid Sequence; Animals; Child; Child, Preschool; Coloboma; Developmental Disabilities; Female; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Microfilament Proteins; Mutation, Missense; Nuclear Proteins; Sequence Homology; Syndrome; WD40 Repeats; Zebrafish
PubMed: 31327510
DOI: 10.1016/j.ajhg.2019.06.015 -
The British Journal of Ophthalmology Feb 2003To phenotype and genetically map the disease locus in a family presenting with autosomal dominant microcornea, rod-cone dystrophy, cataract, and posterior staphyloma. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
AIM
To phenotype and genetically map the disease locus in a family presenting with autosomal dominant microcornea, rod-cone dystrophy, cataract, and posterior staphyloma.
METHODS
Six affected and three unaffected members of the pedigree were examined. All individuals provided a history and underwent a full clinical examination with A-scan and B-scan ultrasonography and electrophysiological testing where appropriate. PCR based microsatellite marker genotyping using a positional candidate gene approach was then performed on DNA samples extracted from venous blood provided by each subject.
RESULTS
The disorder is inherited as an autosomal dominant trait with variable expressivity and has a complex phenotype. Affected individuals had bilateral microcornea, pulverulent-like lens opacities, a rod-cone dystrophy and posterior staphyloma (MRCS). Using a positional candidate gene approach, the authors have evidence suggestive of linkage of this disorder to a region on 11q13 within the nanophthalmos 1 (NNO1) genetic interval. The small family size militates against achieving a LOD score of 3, but the haplotype data and the position of the putative MRCS locus within a known nanophthalmos locus are suggestive of linkage. A candidate gene within this region (ROM1) was screened and no mutations were found in affected members of the family.
CONCLUSION
This rare developmental disorder has some phenotypic similarities to nanophthalmos and possibly maps to a locus within the genetic interval encompassing the NNO1 locus. Screening of candidate genes within this region continues.
Topics: Adolescent; Adult; Cataract; Child; Chromosome Disorders; Cornea; DNA; Female; Genetic Linkage; Genetic Markers; Genotype; Humans; Male; Middle Aged; Mutation; Pedigree; Phenotype; Retinitis Pigmentosa; Scleral Diseases; Syndrome
PubMed: 12543751
DOI: 10.1136/bjo.87.2.197 -
Human Mutation Apr 2018Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other... (Review)
Review
Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.
Topics: Animals; Cataract; Eye Abnormalities; Facies; Forkhead Transcription Factors; Growth Disorders; Hearing Loss, Sensorineural; Heat Shock Transcription Factors; Homeodomain Proteins; Humans; Intellectual Disability; Mutation; Proto-Oncogene Proteins c-maf; Transcription Factors
PubMed: 29314435
DOI: 10.1002/humu.23395 -
American Journal of Human Genetics May 2008Several dysmorphic syndromes affect the development of both the eye and the ear, but only a few are restricted to the eye and the external ear. We describe a...
Several dysmorphic syndromes affect the development of both the eye and the ear, but only a few are restricted to the eye and the external ear. We describe a developmental defect affecting the eye and the external ear in three members of a consanguineous family. This syndrome is characterized by ophthalmic anomalies (microcornea, microphthalmia, anterior-segment dysgenesis, cataract, coloboma of various parts of the eye, abnormalities of the retinal pigment epithelium, and rod-cone dystrophy) and a particular cleft ear lobule. Linkage analysis and mutation screening revealed in the first exon of the NKX5-3 gene a homozygous 26 nucleotide deletion, generating a truncating protein that lacked the complete homeodomain. Morpholino knockdown expression of the zebrafish nkx5-3 induced microphthalmia and disorganization of the developing retina, thus confirming that this gene represents an additional member implicated in axial patterning of the retina.
Topics: Aged; Animals; Consanguinity; Ear; Embryo, Mammalian; Embryo, Nonmammalian; Eye Abnormalities; Female; Fetus; Homeodomain Proteins; Humans; Male; Mice; Middle Aged; Molecular Sequence Data; Organ Specificity; Pedigree; Syndrome; Transcription Factors; Zebrafish
PubMed: 18423520
DOI: 10.1016/j.ajhg.2008.03.007 -
The British Journal of Ophthalmology Sep 1967
Topics: Child; Choroid; Coloboma; Cornea; Eye Abnormalities; Female; Humans; Iris; Microphthalmos; Myopia; Pedigree
PubMed: 4963695
DOI: 10.1136/bjo.51.9.627 -
Ocular Oncology and Pathology Oct 2016Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include...
BACKGROUND
Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include posterior embryotoxon, mosaic pattern of iris stromal hypoplasia, microcornea, optic disc drusen, and pigmentary retinopathy. We present the second report of ocular pathology in two cases of Alagille syndrome.
METHODS
Gross and histologic preparations of four eyes of two patients.
RESULTS
Posterior embryotoxon is seen in both cases, with iris processes extending to the embryotoxon in case 1. Case 1 exhibited distinctly abnormal iris stroma with a prominent cleft separating the anterior and posterior stroma. Lacy vacuolization of the iris pigment epithelium was seen in case 2.
CONCLUSIONS
Alagille syndrome is primarily a hepatic disorder but presents with several distinct ocular pathologic features, most specifically posterior embryotoxon. This and the unusual iris stroma may be caused by improper migration of neural crest cells due to mutation in the gene that causes Alagille syndrome. Patients with Alagille syndrome rarely present to ocular autopsy. Pathology findings may help us better understand the pathophysiology of the ocular abnormalities in this disorder.
PubMed: 27843908
DOI: 10.1159/000446804 -
BMJ Case Reports May 2022
Topics: Choroid; Coloboma; Eye Abnormalities; Humans; Retina; Retinal Diseases
PubMed: 35606024
DOI: 10.1136/bcr-2021-245848 -
Investigative Ophthalmology & Visual... Mar 2020To 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...
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.
Topics: Animals; Animals, Newborn; Cataract; Cell Differentiation; Cell Proliferation; Cells, Cultured; Connexins; Corneal Diseases; Epithelial Cells; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Lens, Crystalline; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Microscopy, Fluorescence; Point Mutation
PubMed: 32182330
DOI: 10.1167/iovs.61.3.25