Hb Sitia β128(H6)Ala → Val was found in a Greek female with slightly reduced red blood cell indices. The abnormal hemoglobin was indistinguishable from Hb A by electrophoresis but eluted after Hb A ...on cation exchange high performance liquid chromatography. DNA sequence analysis revealed a GCT → GTT mutation at codon 128, which is predicted to encode an Ala → Val substitution. This was confirmed by mass spectrometry analyses of the β-globin chain. Since alanine at β128(H6) interacts with several amino acids of the α1β1 contact, its replacement by a larger residue results in a mild instability of the molecule and slight modifications of the oxygen binding properties.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a frequency of 1 in 500 in most western populations. It is characterized by hypercholesterolemia, which predisposes to the ...formation of tendon xanthomas and artherosclerotic plaques, increasing the risk of coronary artery disease (CAD) and premature death from myocardial infarction, often before the age of 55 years in FH heterozygotes and within the first two decades of life in the rare FH homozygotes (Goldstein and Brown, 1979). FH is usually caused by dysfunction of the low-density lipoprotein receptor (LDLR) protein, which in its mature form is a transmembranal protein of 839 amino acids. The LDLR gene is located on the distal short arm of chromosome 19, is 45 kb in length and has 18 exons (Yamamoto et al., 1984); to date more than 150 LDLR gene defects have been described in individuals with FH (Hobbs et al., 1992). They include large gene rearrangements (deletions or insertions), missense, nonsense and frame shift mutations. In most populations there is a general diversity of mutations, although in certain populations small numbers of mutations predominate due to a founder effect (Hobbs et al., 1992). In Greece, there have been substantial biochemical and epidemiological studies on FH, but so far the molecular basis has not been investigated. This report describes the initial results of a study to characterize the spectrum of LDLR mutations in Greece.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an ...available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C > T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Homozygous β-thalassemia is usually characterized by severe anemia requiring regular blood transfusion for survival. For homozygous patients with milder clinical manifestations and no dependence on ...transfusion therapy, the term thalassemia intermedia is usually applied. Genetic mechanisms that may ameliorate the clinical expression of homozygous β-thalassemia include coinheritance of α-thalassemia, inheritance of mild β-globin gene mutations, and increased γ-globin chain production, which may partially compensate for the lack of β-globin chain synthesis. To identify which of these factors may contribute to the modification of childhood homozygous, high-hemoglobin A2 (HbA2) β-thalassemia in Greece, the interaction of α-thalassemia, types of β-thalassemia mutations, and the presence of a polymorphic site 5′ to the Gγ-globin gene, which has been described as associated with increased γ-globin chain production in some cases, was assessed. The results were analyzed in light of similar studies in 150 randomly selected, homozygous, high-HbA2 β-thalassemia patients with the aim of assessing whether thalassemia genotypes can provide information useful for prognosis and/or more appropriate management of homozygous β-thalassemia patients. The results indicate that, in general, the major factor modifying the clinical expression of homozygous, high-HbA2 β-thalassemia in Greece is the inheritance of mild β-thalassemia mutations. Although there is not always a complete correlation of genotype with clinical phenotype, the inheritance of two mild β-thalassemia alleles results in almost all cases (11 of 12 cases in this study) in thalassemia intermedia phenotype. Therefore, the characterization of β-globin gene mutations may be useful in some cases for evaluation of prognosis and/or prescription of treatment in Greek thalassemia intermedia children.
Two novel CFTR mutations were detected in Greek cystic fibrosis patients. One was a missense mutation, A46D, and the other a splice mutation, 296 + 1G − C. Neither was detected on normal chromosomes.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have screened 175 patients for molecular defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene using nondenaturing polyacrylamide gel electrophoresis (PAGE), denaturing ...gradient gel electrophoresis (DGGE), and sequencing. Six different mutations (F508del, G542X, 621+1G --> T, 2789+5G --> A, R1070Q, and S466X) accounted for 79.71% of CF alleles, with the F508del mutation showing a frequency of 72.28%. Another 12 mutations (R334W, 2184insA, I507del, 1525-1G --> A, E585X, R75X, M1I, 457TAT --> G, 574delA, 2723delTT, A120T, and 2907delTT) covered an additional 3.36%. A novel mutation (2723delTT) was found in one CF patient (F508del/2723delTT). Thus, a total of 18 mutations cover 82.57% of CF alleles. During our study, 72% of families at risk for having a CF child were found to be fully informative for prenatal diagnosis. Prenatal diagnosis was performed on 56 families; 76 analyses resulting in 16 affected, 38 carriers, and 22 healthy fetuses. These results imply that the molecular basis of CF in Serbia and Montenegro is highly heterogeneous, as is observed in other eastern and southern European populations. Because we detected more then 80% of CFTR alleles, results could be used for planning future screening and appropriate genetic counseling programs in our country.
In this study, we report the further results of an ongoing project on the delineation of the spectrum of mutations on the ATP7B gene in Wilson disease (WD) patients of Greek origin. We have analyzed ...24 additional families and detected 16 mutations (five frameshifts, two splice site, two nonsense, and seven missense), of which six are novel. On adding these results to the ones already published by us, we conclude that WD shows a marked allelic heterogeneity in the Greek population. Of the total number of mutations so far detected, the most common eight account for the molecular defect in 72.8% of the WD chromosomes. The most frequent mutation is the His0169Gln, which has a frequency of 28.5%, similar to those reported in North European populations. Using these data, an efficient strategy of mutation screening for WD is possible in this population, thus improving the possibility of preclinical diagnosis.
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