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      Novel L558P Mutation of the TGFBI Gene Found in Ukrainian Families with Atypical Corneal Dystrophy

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          Purpose: To report a novel L558P mutation of the human transforming growth factor β-induced (TGFBI) gene found in Ukrainian families with atypical corneal dystrophy (CD). Methods: Genomic DNA was extracted from peripheral leukocytes of 12 members of 4 unrelated families with atypical CD. We performed genotype analysis of these families with microsatellite markers surrounding the TGFBI locus. Exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and directly sequenced in 5 patients of 4 unrelated families. We utilized a simple PCR/restriction fragment length polymorphism-based technique for L558P mutation identification. Fifty normal individuals were also analyzed as controls. These assays were complemented by histological analysis of available corneal buttons excised during penetrating keratoplasty. Results: A heterozygous single-base-pair transition (CTC to CCC, leucine to proline) at codon 558 in exon 12 of the TGFBI gene (L558P) was detected in 10 individuals. Eight are affected, and 2 are teenagers with no clinical manifestation of the disease as yet. The mutation was not found in 2 healthy individuals from 2 high-risk CD families, nor in 50 normal controls. Histopathological examination identified amyloid deposits, mostly in the posterior central cornea. Haplotype analysis provided evidence of a common founder of the L558P mutation. The mutation works on the protein level by disrupting an α-helix, which is crucial for the normal functioning of keratoepithelin. Conclusion: A novel L558P mutation in the TGFBI gene causes an atypical type of stromal CD.

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          Most cited references 9

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          Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat.

           F Neuhuber,  B Rolf,  J Hühne (1998)
          In 10,844 parent/child allelic transfers at nine short-tandem-repeat (STR) loci, 23 isolated STR mismatches were observed. The parenthood in each of these cases was highly validated (probability >99.97%). The event was always repeat related, owing to either a single-step mutation (n=22) or a double-step mutation (n=1). The mutation rate was between 0 and 7 x 10(-3) per locus per gamete per generation. No mutations were observed in three of the nine loci. Mutation events in the male germ line were five to six times more frequent than in the female germ line. A positive exponential correlation between the geometric mean of the number of uninterrupted repeats and the mutation rate was observed. Our data demonstrate that mutation rates of different loci can differ by several orders of magnitude and that different alleles at one locus exhibit different mutation rates.
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            Kerato-epithelin mutations in four 5q31-linked corneal dystrophies.

            Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the beta ig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.
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              Mutation patterns at dinucleotide microsatellite loci in humans.

               Zhong Liu,  Jin Li,  Hui Shen (2002)
              Microsatellites are a major type of molecular markers in genetics studies. Their mutational dynamics are not clear. We investigated the patterns and characteristics of 97 mutation events unambiguously identified, from 53 multigenerational pedigrees with 630 subjects, at 362 autosomal dinucleotide microsatellite loci. A size-dependent mutation bias (in which long alleles are biased toward contraction, whereas short alleles are biased toward expansion) is observed. There is a statistically significant negative relationship between the magnitude (repeat numbers changed during mutation) and direction (contraction or expansion) of mutations and standardized allele size. Contrasting with earlier findings in humans, most mutation events (63%) in our study are multistep events that involve changes of more than one repeat unit. There was no correlation between mutation rate and recombination rate. Our data indicate that mutational dynamics at microsatellite loci are more complicated than the generalized stepwise mutation models.

                Author and article information

                S. Karger AG
                May 2009
                17 February 2009
                : 223
                : 3
                : 207-214
                aDepartment of Human Genomics, Institute of Molecular Biology and Genetics, National Academy of Science of Ukraine, Kyiv, and bFilatov Institute of Eye Diseases and Tissue Therapy, Academy of Medical Science of Ukraine, Odesa, Ukraine
                202645 Ophthalmologica 2009;223:207–214
                © 2009 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 3, References: 21, Pages: 8
                Original Paper

                Vision sciences, Ophthalmology & Optometry, Pathology

                Mutation analysis, Corneal dystrophy, TGFBI gene


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