Novel L558P mutation of the TGFBI gene found in Ukrainian families with atypical corneal dystrophy.

PURPOSE: To report a novel L558P mutation of the human transforming growth factor beta-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 alpha-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.

Analysis of CCR5Delta32 geographic distribution and its correlation with some climatic and geographic factors.

We studied the possible effects of climatic-geographic factors on the world distribution of the mutant allele for the chemokine receptor gene CCR5, which has a 32-bp deletion (CCR5Delta32) preventing cell invasion by the primary transmitting strain of HIV-1. New data on CCR5 polymorphisms in Russian, Ukrainian, and Moldavian populations are presented. All available data on CCR5Delta32 frequencies in the Old World (number of populations n = 77) were used for construction of a geographical gene map to analyze possible correlations between allele frequencies and eight climatic-geographic parameters. A strong positive correlation was found between the allele frequency and latitude (r = 0.72), a strong negative correlation with annual radiation balance (r = -0.66), and a weaker negative correlation with longitude (r = -0.34). Partial correlations were calculated excluding the influence of latitude. The negative correlation between the allele frequency and annual radiation balance decreased (r = -0.42), but remained large and significant. We propose that the existence of correlations between the cline of CCR5Delta32 frequencies and climatic-geographic parameters provides evidence for a possible effect of either natural environmental factors or large-scale population movements on the distribution of this allele.