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Developmental disorders of the lens and anterior segment of the eye
Jedličková, Jana ; Ďuďáková, Ľubica (advisor) ; Šafka Brožková, Dana (referee) ; Cvekl, Ales (referee)
The anterior segment of the eye includes the eyelids, eyelashes, tear film, cornea, conjunctiva, iris, pupil, ciliary body, chamber angle, and lens. Cataracts and anterior segment dysgenesis are a highly heterogeneous group of diseases exhibiting all types of Mendelian inheritance. The aim of this thesis was molecular genetic analysis of 51 patients from 23 families with congenital and early onset cataracts and/or anterior segment dysgenesis, using a modern as well as conventional methods, such as next-generation sequencing, direct sequencing, bioinformatic and functional analyses including the use of artificial splicing vectors. We identified 24 causal variants in the coding, non-coding and regulatory regions of the PAX6, FTL, FOXC1, PITX2, FOXE3, and CHRDL1 genes. We confirmed the role of the n.37C>T variant in MIR204 in the development of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma. Splicing assay confirmed pathogenic effect of two mutations on pre-mRNA splicing of the PAX6 gene. Establishing molecular genetics diagnosis improves patient counselling and their relatives in terms of the prognosis and risk of developing secondary glaucoma Key words: molecular-genetic diagnosis, anterior segment dysgenesis, next-generation sequencing,...
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Anterior segment dysgenesis disorders and their molecular genetic cause
Moravíková, Jana ; Lišková, Petra (advisor) ; Krulová, Magdaléna (referee)
Proper eye development depends on expression and mutual regulation of many genes. Anterior segment dysgenesis (ASD) are a highly heterogeneous group of diseases exhibiting all types of Mendelian inheritance, which manifest as combination of congenital abnormalities of the cornea, iris, anterior chamber angle or lens. Screening of genes associated with ASD does not often lead to the identification of the underlying genetic cause implying that there are still novel variants or genes to be discovered. Molecular genetic analysis in 12 probands with ASD using Sanger and whole-exome sequencing were performed. Functional analysis by Exon trapping assay was provided in variants predicted to effect pre-mRNA splicing. Four PAX6 mutations evaluated as pathogenic or likely pathogenic in a heterozygous state were found in four probands c.183C˃G; p.(Tyr61*), c.1032+1G>A, c.1183+1G>T and c.622C>T; p.(Arg208Trp). One proband was found to be a compound heterozygote for c.244A>G; p.(Met82Val) and c.541delG; p.(Glu181Lysfs*26) mutations in FOXE3. In 7 probands, no potentially pathogenic variants were identified. Exon trapping assay confirmed that mutations c.1032+1G>A and c.1183+1G>T have an effect on pre-mRNA splicing of the PAX6 gene. Detailed molecular-genetic analysis in patients with ASD may contribute to...
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Anterior segment dysgenesis disorders and their molecular genetic cause
Moravíková, Jana ; Lišková, Petra (advisor) ; Krulová, Magdaléna (referee)
Proper eye development depends on expression and mutual regulation of many genes. Anterior segment dysgenesis (ASD) are a highly heterogeneous group of diseases exhibiting all types of Mendelian inheritance, which manifest as combination of congenital abnormalities of the cornea, iris, anterior chamber angle or lens. Screening of genes associated with ASD does not often lead to the identification of the underlying genetic cause implying that there are still novel variants or genes to be discovered. Molecular genetic analysis in 12 probands with ASD using Sanger and whole-exome sequencing were performed. Functional analysis by Exon trapping assay was provided in variants predicted to effect pre-mRNA splicing. Four PAX6 mutations evaluated as pathogenic or likely pathogenic in a heterozygous state were found in four probands c.183C˃G; p.(Tyr61*), c.1032+1G>A, c.1183+1G>T and c.622C>T; p.(Arg208Trp). One proband was found to be a compound heterozygote for c.244A>G; p.(Met82Val) and c.541delG; p.(Glu181Lysfs*26) mutations in FOXE3. In 7 probands, no potentially pathogenic variants were identified. Exon trapping assay confirmed that mutations c.1032+1G>A and c.1183+1G>T have an effect on pre-mRNA splicing of the PAX6 gene. Detailed molecular-genetic analysis in patients with ASD may contribute to...
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