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We report a novel β+-thalassemia mutation found in a Vietnamese family. The molecular defect T→A lies at -72 of the β-globin gene promoter, within the conserved CCAAT box. The index case was a 5-year-old child having red blood cells indices close to normal and slightly increased level of HbA2 (3.96%). The expression of the mutated β allele was inferred by luciferase reporter assay in K562 cells. The β -72 determinant is the eighth β-thalassemic mutation identified in Vietnam and it was not previously reported in any population. The absence of homozygous or compound heterozygous states did not allow us to precisely predict either its clinical impact or its relevance in management programs. Our results further underline the importance of identifying and characterizing new or rare β+-thalassemic alleles in carrier screening and prenatal diagnosis. [ABSTRACT FROM AUTHOR]

During a screening for hemoglobinopathies, we found a carrier of the Sardinian ββ-thalassemia condition. The proband's hematology and hemoglobin (Hb) profile agreed with those of the other carriers previously identified during our diagnostic program except for the fetal Hb (HbF) composition, which consisted of both α2 Aγ2 and α2 Gγ2 instead of nearly 100% α2 Aγ2 . In order to explain the unusual γ-chain ratio, sequencing of the Gγ promoter was carried out and revealed two nucleotide substitutions in cis : C → T at position -474 and A → G at position -309 from the Cap site. The latter had previously been observed in subjects with raised HbF levels, although it has not yet been evaluated at functional level. We used the luciferase assay to determine whether the two mutations modify the transcriptional activity of the Gγ promoter. Results indicated that the observed in vivo Gγ- globin production cannot be translated into increased in vitro promoter function, suggesting that the assessed muta- tions cannot be considered as functional single nucleotide polymorphisms per se; instead, a more complex regulatory mechanism might be involved. [ABSTRACT FROM AUTHOR]

A new variant of the fetal hemoglobin (Hb) was observed in a newborn baby subjected to phototherapy due to jaundice, by means of electrophoretic and chromatographic techniques. The variant Hb resulted unstable by the isopropanol stability test. After HBG2 gene sequencing, the G to A transversion at codon 64, position eight of the E helix, was found, which corresponds to the Asp for Gly amino acid substitution. The new variant was called Hb F-Turritana [Gγ64(E8)Gly→Asp, HBG2:c.194G>A]. Incoming aspartic acid residue, bulky and negatively charged, may be responsible for alteration of the heme pocket steric configuration and for instability. The new abnormal HBG2 gene was found to be associated in cis with the mutated HBG1 gene, which characterizes the Hb F-Sardinia [Aγ (E19)Ile→Thr, HBG1:c.227T>C] variant. [ABSTRACT FROM AUTHOR]

Here we describe Hb F-Avellino [Gγ41(C7)Phe → Leu;HBG2: c.124 T > C], a new hemoglobin (Hb) variant observed in a healthy newborn. The proband’s hemolysate was found to be mildly unstable by the isopropanol test. The occurrence of the variant was assessed by both chromatographic and electrophoretic methods. DNA sequencing analysis of theGγ gene showed a T to C transition at codon 41 (TTC > CTC) corresponding to the Phe → Leu substitution. Normal functional properties have been hypothesized. [ABSTRACT FROM PUBLISHER]

Two healthy newborns, heterozygous for two different γ-globin chain mutations, were observed during an electrophoretic screening for hemoglobinopathies in Sassari, North Sardinia (Italy). The variants were characterized by reversed phase high performance liquid chromatography (HPLC) and sequencing of amplified γ-globin genes. One of the two abnormalities was a novel Aγchain variant and the tetramer was named Hb F-Osilo [Aγ119(GH2)Gly→Ser]. The other was a Gγ chain variant, Hb F-Paulinia [Gγ80(EF4)Asp→Tyr], already described in a Brazilian baby of African ancestry. No functional studies could be performed. [ABSTRACT FROM AUTHOR]

We report a new hemoglobin (Hb) variant on theHBA2gene, Hb Zara [α91(FG3)Leu→Ile (α2);HBA2: c.274C > A], which was found in a Caucasian man from Croatia. It was observed by routine cation exchange chromatography as an abnormal 21.8% fraction overlapping Hb A2, and associated with normal hematology. It was slightly unstable by the standard isopropanol precipitation test. DNA analysis revealed theCTT > ATT mutation at codon 91 on an α2 gene of a normal α-globin gene arrangement. This new variant represents the sixth described mutation at codon α91 and fourth on the α2 locus. As a result of the slight instability due to the significant role of the α91 residue in the α1β2 contact, the level of the Hb Zara variant was lower than levels observed for several stable variants codified by the α2 locus. [ABSTRACT FROM AUTHOR]

Hb F-Emirates [ G ?59(E3)Lys?Glu] was first described in a newborn from the United Arab Emirates. Here we describe the occurrence of this variant in a family of Sardinian ancestry. Direct DNA sequencing analysis of the selectively amplified G ? gene shows that the AAA?GAA transition, corresponding to a Lys?Glu substitution, is responsible for this abnormal hemoglobin (Hb). Our observation indicates a multiple origin of the mutation. In order to facilitate future studies at the level of population genetics, the structure of the entire G ? gene that carries the mutation was assessed and compared with that of normal G ? genes. [ABSTRACT FROM AUTHOR]

The abnormal Hb F-Porto Torres [Aγ75(E19)Ile→Thr, 136(H14)Ala→Ser] was observed during a cord blood survey for hemoglobinopathies in North Sardinia. This silent variant showed the same mobility as Hb F-Sardinia in isoelectric focusing (LEF) of the tetramers, whereas the abnormal globin chain was clearly separated by acid- urea-Triton polyacrylamide gel electrophoresis (AUT-PAGE) from the normal Gγ- and Aγ-globin chains. Separation of the globin chains by reversed phase high performance liquid chromatography (HPLC) indicated the following percentages: Gγ 68.4, Aγ 14.0, Xγ 17.6, that strongly suggested the abnormal chain as being a variant of the Aγ-globin. Sequencing of the γ-globin genes indicated that the mutated gene was in fact an Aγ with two nucleotide replacements, one being the ATA→ACA (Ile→Thr) at codon 75 (the so-called AγT of the rather common Hb F-Sardinia) and the second the GCA→JCA (Ala→Ser) at codon 136. This new variant is the seventh having the sequence of the AγT chain with an additional mutation so far described and the third characterized by gene sequencing. [ABSTRACT FROM AUTHOR]

Four novel alleles of the adult β-globin gene of Capra hircus were observed in an extended study on hemoglobin polymorphism in goat breeds living in the island of Sardinia. Nucleotide sequencing showed that one of these alleles is due to a 2 bp substitution at codon 125 (&CTdline;G → &GAdline;G, Leu → Glu). Two substitutions, the silent CT&Tdline; → C T&Cdline; for Leu at codon 78 and the conservative A&Adline;G → A&Gdline;G (Lys → Arg) at codon 104, are shared by the other three alleles, two of them having additional mutations, which suggests a common origin. The allele we provisionally called the β[supY] shares four out of five amino acid substitutions, together with the same polymorphisms in the IVSII, we observed previously in the rather common gene. This evidence allowed the origin of the β[supE] gene to be better characterized. The data increase to seven the number of alleles at the goat β[supA]-globin locus characterized thus far at the molecular level. A simplified nomenclature for the increasing number of goat β-globin alleles is presented. [ABSTRACT FROM AUTHOR]

Abstract: Background: HbF-Monserrato-Sassari is a newly discovered abnormal fetal hemoglobin observed in an apparently normal newborn baby during a hemoglobinopathies survey at birth in North Sardinian population. Methods: Electrophoretic analysis of the cord blood lysate evidenced for an abnormal tetramer due to a mutated fetal globin chain. Electrospray ionisation-mass spectrometry and gene sequencing were used to identify the mutation. Oxygen binding ability of the variant Hb was determined. Results: Sequencing of the γ globin genes revealed the TGT→ CGT transition at codon 93 in one of the two Gγ genes, which leads to the Arg for Cys amino acid replacement at position 9 of the F α-helix. The amino acid substitution was confirmed by mass spectrometric analysis of the globin chains. Since modifications or substitutions at position β93 are known to affect the arrangement of a salt bridge at the α1β2 sliding contacts that are crucial for subunit cooperativity, the functional properties of the variant were studied to evaluate the effect of the replacement at the same position in the γ globin chain. With respect to normal HbF, the variant showed a significant increase in oxygen affinity and a slight decrease of both Bohr effect and cooperativity. General significance: Result indicates a key role of the Cys γ93 residue for subunit cooperativity in the T→R transition of the HbF tetramer. Substitutions at the F9 position of the Gγ globin may result in stabilization of the high affinity R-state of the Hb tetramer. Because of the loss of Cys γ93 residue, this variant is considered to be potentially compromised in nitric oxide transport. [Copyright &y& Elsevier]

Once widespread in their homelands, the Anatolian mouflon (Ovis gmelini anatolica) and the Cyprian mouflon (Ovis gmelini ophion) were driven to near extinction during the 20th century and are currently listed as endangered populations by the International Union for Conservation of Nature. While the exact origins of these lineages remain unclear, they have been suggested to be close relatives of domestic sheep or remnants of proto-domestic sheep. Here, we study whole genome sequences of n = 5 Anatolian mouflons and n = 10 Cyprian mouflons in terms of population history and diversity, comparing them with eight other extant sheep lineages. We find reciprocal genetic affinity between Anatolian and Cyprian mouflons and domestic sheep, higher than all other studied wild sheep genomes, including the Iranian mouflon (O. gmelini). Studying diversity indices, we detect a considerable load of short runs of homozygosity blocks (<2 Mb) in both Anatolian and Cyprian mouflons, reflecting small effective population size (Ne). Meanwhile, Ne and mutation load estimates are lower in Cyprian compared with Anatolian mouflons, suggesting the purging of recessive deleterious variants in Cyprian sheep under a small long-term Ne, possibly attributable to founder effects, island isolation, introgression from domestic lineages, or differences in their bottleneck dynamics. Expanding our analyses to worldwide wild and feral Ovis genomes, we observe varying viability metrics among different lineages and a limited consistency between viability metrics and International Union for Conservation of Nature conservation status. Factors such as recent inbreeding, introgression, and unique population dynamics may have contributed to the observed disparities., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

We report a novel β + -thalassemia mutation found in a Vietnamese family. The molecular defect T→A lies at -72 of the β -globin gene promoter, within the conserved CCAAT box. The index case was a 5-year-old child having red blood cells indices close to normal and slightly increased level of HbA 2 (3.96%). The expression of the mutated β allele was inferred by luciferase reporter assay in K562 cells. The β -72 determinant is the eighth β -thalassemic mutation identified in Vietnam and it was not previously reported in any population. The absence of homozygous or compound heterozygous states did not allow us to precisely predict either its clinical impact or its relevance in management programs. Our results further underline the importance of identifying and characterizing new or rare β + -thalassemic alleles in carrier screening and prenatal diagnosis.