The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3′ end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Gγ-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T β-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases

Classification and structure of echovirus 5 '-UTR sequences

Enteroviruses are classified into two genetic clusters on the basis of 5'-UTR and all echoviruses (ECV) are classified together with coxsackie B viruses (CBV), coxsackie A viruses (CAV) types 2-10, 12, 14 and 16, and enteroviruses (EV) 68, 69, 71 and 73. During the present study, 5'-UTR-derived sequences constituting the largest part of the Internal Ribosome Entry Site (IRES) of ECVs were studied with respect to their possible secondary structures, which were predicted following the phenomenon of "covariance", i.e. the existence of evolutionary pressure in favour of structural conservation in the light of nucleotide sequence variability. In this and previous studies, no correlation between overall 5'-UTR identity and the currently recognised Human Enterovirus species was found, implying that notwithstanding their divergent protein-encoding regions, these species are free to exchange 5'-UTRs by recombination. Secondary structure features which are known to be highly conserved amongst enteroviruses and specifically the GNRA tetraloop in secondary structure domain IV, involved in long-term tertiary interactions and loop B in secondary structure domain V with an as yet unknown function were also conserved in ECVs. In contrast, the C(NANCCA)G motif, which is considered to be important in virus transcription and translation, was not conserved in all ECVs and sequence patterns observed in other enterovirus groups and rhinoviruses were recorded

Readressing the Role of Toll-Like Receptor-4 Alleles in Inflammatory Bowel Disease: Colitis, Smoking, and Seroreactivity

Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles