A New α1-Globin Variant, Hb Ormylia [HBA1:c.63C > G; p.His21Gln]. Report of Eleven Cases in Northern Greece.

The first identification of a novel α1-Globin variant, Hb Ormylia in 11 Greeks originating from a small village, Ormylia, Chalkidiki, Greece is reported. The new genetic variant leads to the production of a hemoglobin variant that can be identified and quantified by High-Performance Liquid Chromatography. Capillary and classic electrophoresis were not informative. Direct DNA sequencing revealed a new mutation C > G mutation at codon 21 of α1 gene (His > Gln). The new variant has been named Hb Ormylia and this is the first description of this genetic variant of α1 gene in the literature.

High-Oxygen-Affinity Hemoglobins-Case Series and Review of the Literature.

Modifications of the hemoglobin (Hb) structure in regions involving the regulation of oxygen transport may lead to an increased oxygen affinity for the hemoglobin molecule and impaired oxygen delivery to the tissues. Herein, we present six patients with high-oxygen-affinity Hb variants, either in heterozygous form or in compound heterozygosity (such as heterozygosity for Hb Hiroshima, Köln, Crete, and compound heterozygosity Hb Crete with ß or 뫧 thalassemia), in order to demonstrate the need for prompt and accurate diagnosis and enrich the limited literature due to the rarity of such cases. Hb Crete, Hb Hiroshima, and Hb Köln have distinct pathophysiologies and may result in different clinical phenotypes. In conclusion, high-oxygen-affinity hemoglobins are rare and inherited within a dominant autosomal manner, have various clinical presentations, and should always be suspected in patients with erythrocytosis. Their management (as phlebotomy or low-dose aspirin) should be based on an individualized assessment of the risk of complications, the medical history, concomitant symptoms, and quality of life.

Rare Pathogenic ß0-Thalassemia Mutation, Codon 7 (GAG>TAG) (HBB: c.22G>T). Report of the First Two Cases in Albanian Immigrants of Northern Greece.

We report the hematological data of the codon 7 (GAG>TAG (HBB: c.22G>T) mutation for the first time in two Albanian individuals from the region of Elbasan, who underwent genetic testing due to prenatal counseling and diagnosis for ß-thalassemia major (ß-TM) anemia. The phenotype was compatible with a typical ß0-thalassemia (ß0-thal) carrier but the hematological findings of the mutation has not been previously reported. The mutation involves the conversion of codon 7 GAG (Glu) into a translation termination codon (TAG), involving the replacement of guanine by thymine so that no ß chains are produced.

Fetal heterozygosity for both Hb G-Hsi-Tsou and beta thalassemia: A case report.

INTRODUCTION: This case report describes a fetus with compound heterozygosity for Hb G-Hsi-Tsou and beta thalassemia, diagnosed in a healthy pregnancy. To the best of our knowledge, this is the first documented case of compound heterozygosity and the woman is the second known case of heterozygosity for Hb G-Hsi-Tsou. CASE PRESENTATION: A 34-year-old woman during her first pregnancy underwent hemoglobin electrophoresis which revealed heterozygosity for Hb G-Hsi-Tsou. Hemoglobin G-Hsi-Tsou constitutes a hemoglobin variant with a structural abnormality of the beta chain, first described in 1972, but since then no other cases have been reported. After finding out that her husband was heterozygous for beta thalassemia, chorionic villus sampling revealed the embryo's heterozygosity for both Hb G-Hsi-Tsou and beta thalassemia. Due to lack of scientific data, the couple decided to end the pregnancy. CONCLUSION: It was not possible to determine whether the fetus would present serious deficiencies in hematopoiesis, as Hb G-Hsi-Tsou is a variant which is not yet fully understood. What made this case even more complex was the simultaneous presence of the beta thalassemia allele.

Coinheritance of Triplicated Alpha-Globin Gene and Beta-Thalassemia Mutations in Adulthood: Ten Years of Referrals in Northern Greece.

Greece is a country of ~11 million people, where hemoglobinopathies are the most common genetic diseases. The reported data describe the clinical phenotype of cases with coinheritance of triplicated α-globin (anti-α3.7 kb) and ß-globin gene mutations in Northern Greece, that were referred within the last 10 years, in The Adult Thalassemia Unit of "Hippokration" Hospital, Thessaloniki, Northern Greece. The description of specific genotypes of the ß-globin gene mutations in coinheritance with the triplicated α-globin gene (anti-α3.7 kb) and correlation with the hematologic and clinical data in adulthood may be useful in the evaluation of pediatric patients' prognosis and in genetic counseling of couples at risk.

Efficacy of the National Thalassaemia and Sickle Cell Disease Prevention Programme in Northern Greece: 15-Year Experience, Practice and Policy Gaps for Natives and Migrants.

Hemoglobinopathies constitute the most frequent monogenic disorders worldwide and in Greece. In Greece, carrier frequency is estimated at about 8.0%, resulting in a heavy disease burden in the past. Therefore, the implementation of a national prevention program of the disease was an urgent necessity. Moreover, due to migration flow from different geographic areas in the last two decades, the observed spectrum of underlying mutations was expanded, leading to the adaptation of diagnostic approaches. We report the results of the National Thalassaemia Prevention Programme in Northern Greece, over a 15-year period (2001-2015). In total 33,837 healthy at-risk individuals (individuals or couples, 91.0% Greeks) were screened. We have screened 1598 pregnancies in 371 (23.0%) (10.0% non Greeks), of whom both parents carried gene defects and were offered genetic counseling. Seventy-six fetuses (23.0%) were predicted to be affected by severe forms of the disease. Following informed parental choices, 73 of the above pregnancies were terminated. Meanwhile, within the study period, 58 new thalassemic babies (five non Greeks) were referred to the Thalassaemia and Sickle Cell Disease Care Unit of Northern Greece, reflecting mostly parental unawareness, choice or the program failure. Based on the region's population, the birth rate and the prevalence of the disease, the anticipated number of new cases is about 45 annually. According to our data, four thalassemic newborns were registered annually at a stable rate in the last 15 years, reaching a reduction of 90.0% of new affected births. Overall, the National Thalassaemia Prevention Programme effectively decreased the incidence of affected newborns in our region.

Compound Heterozygosity for Hb Adana (HBA2: c.179G>A) and the -α3.7/αα Thalassemia Deletion in Greece: Clinical Phenotype and Genetic Counseling.

Hb Adana (HBA2: c.179G>A) is found worldwide but is extremely rare and carriers are asymptomatic, with red cell indices similar to α+-thalassemia (α+-thal) carriers. First line screening tests are unable to detect the unstable hemoglobin (Hb). Coinheritance with the α-thal (-α3.7) deletion is herein presented and the challenges involving genetic counseling of couples carrying the mutations are discussed.

Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women.

Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.

Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system.

Heat shock protein HSP90 plays important roles in cellular regulation, primarily as a chaperone for a number of key intracellular proteins. We report here that the two HSP90 isoforms, alpha and beta, also localize on the surface of cells in the nervous system and are involved in their migration. A 94-kDa surface antigen, the 4C5 antigen, which was previously shown to be involved in migration processes during development of the nervous system, is shown to be identical to HSP90alpha using mass spectrometry analysis. This identity is further confirmed by immunoprecipitation experiments and by induction of 4C5 antigen expression in heat shock-treated embryonic rat brain cultures. Moreover, immunocytochemistry on live cerebellar rat cells reveals cell surface localization of both HSP90alpha and -beta. Cell migration from cerebellar and sciatic nerve explants is inhibited by anti-HSP90alpha and anti-HSP90beta antibodies, similarly to the inhibition observed with monoclonal antibody 4C5. Moreover, immunostaining with rhodamine-phalloidin of migrating Schwann cells cultured in the presence of antibodies against both alpha and beta isoforms of HSP90 reveals that HSP90 activity is associated with actin cytoskeletal organization, necessary for lamellipodia formation.

The 4C5 antigen is associated with Schwann cell migration during development and regeneration of the rat peripheral nervous system.

The monoclonal antibody 4C5 recognizes a cell surface antigen of the developing central nervous system (CNS) and peripheral nervous system (PNS). In vitro antibody perturbation experiments have shown that the 4C5 antigen is involved in horizontal and vertical migration processes of granule cells during development of the rodent cerebellum. Moreover, results concerning the cellular localization and temporal expression of the 4C5 antigen during development and after injury of the rat sciatic nerve suggested that it may participate in Schwann cell migrations that occur during the above processes. To test this possibility, we examined the effects of our function-blocking antibody on Schwann cell migration in three in vitro bioassays: in tissue cultures from developing sciatic nerve, in dorsal root ganglion cultures on cryostat sections of normal or denervated adult sciatic nerve, and in pure Schwann cell cultures. The results showed that the presence of monoclonal antibody 4C5 in all the above culture systems strongly inhibited Schwann cell migration, indicating that the 4C5 antigen participates in migration processes that take place during development and regeneration of the peripheral nervous system. Moreover, staining of migrating Schwann cells in the presence of monoclonal antibody 4C5 with rhodamine-phalloidin showed that 4C5 antigen activity is associated with actin cytoskeletal organization of these cells, and more specifically with lamellipodia formation.