scholarly journals A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1109-1116 ◽  
Author(s):  
CM de Castro ◽  
B Devlin ◽  
DE Fleenor ◽  
ME Lee ◽  
RE Kaufman
Keyword(s):  
Amino Acid ◽  
Globin Gene ◽  
Point Mutations ◽  
Microcytic Anemia ◽  
Single Amino Acid ◽  
Beta Globin ◽  
Single Nucleotide ◽  
Beta Globin Gene ◽  
Hemoglobin Molecule ◽  
Proline Substitution

Abstract Mutations within exon 3 of the beta-globin gene are relatively uncommon, and many of these mutations produce a dominant thalassemia- like phenotype. We describe a novel thalassemic hemoglobinopathy caused by a single nucleotide substitution (CTG-->CCG) at codon 114 resulting in a leucine to proline substitution and designate it beta Durham-NC [beta 114 Leu-->Pro]. The mutation producing this thalassemic hemoglobinopathy is located near to the beta Showa-Yakushiji mutation (beta 110 Leu-->Pro). Both of these hemoglobinopathies share similar phenotypic features with moderately severe microcytic anemia. Using computer imaging of the hemoglobin molecule, we examined several reported point mutations within exon 3 of the beta-globin gene. These point mutations cause a single amino acid substitution in the G helix, and result in a thalassemic and/or hemolytic phenotype. Computer imaging of nine separate examples suggests that amino acid substitutions affecting side chains that project into the heme pocket may destabilize the heme moiety within the beta-globin chain, resulting in a thalassemic phenotype. Hemolytic phenotypes may be the result of decreased alpha 1 beta 1 interactions. The beta Durham-NC mutation further characterizes a novel group of thalassemias/hemoglobinopathies that are clinically difficult to identify and require accessory laboratory testing.

scholarly journals A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1109-1116 ◽  
Author(s):  
CM de Castro ◽  
B Devlin ◽  
DE Fleenor ◽  
ME Lee ◽  
RE Kaufman
Keyword(s):  
Amino Acid ◽  
Globin Gene ◽  
Point Mutations ◽  
Microcytic Anemia ◽  
Single Amino Acid ◽  
Beta Globin ◽  
Single Nucleotide ◽  
Beta Globin Gene ◽  
Hemoglobin Molecule ◽  
Proline Substitution

Mutations within exon 3 of the beta-globin gene are relatively uncommon, and many of these mutations produce a dominant thalassemia- like phenotype. We describe a novel thalassemic hemoglobinopathy caused by a single nucleotide substitution (CTG-->CCG) at codon 114 resulting in a leucine to proline substitution and designate it beta Durham-NC [beta 114 Leu-->Pro]. The mutation producing this thalassemic hemoglobinopathy is located near to the beta Showa-Yakushiji mutation (beta 110 Leu-->Pro). Both of these hemoglobinopathies share similar phenotypic features with moderately severe microcytic anemia. Using computer imaging of the hemoglobin molecule, we examined several reported point mutations within exon 3 of the beta-globin gene. These point mutations cause a single amino acid substitution in the G helix, and result in a thalassemic and/or hemolytic phenotype. Computer imaging of nine separate examples suggests that amino acid substitutions affecting side chains that project into the heme pocket may destabilize the heme moiety within the beta-globin chain, resulting in a thalassemic phenotype. Hemolytic phenotypes may be the result of decreased alpha 1 beta 1 interactions. The beta Durham-NC mutation further characterizes a novel group of thalassemias/hemoglobinopathies that are clinically difficult to identify and require accessory laboratory testing.

scholarly journals Large Deletions Involving the Beta Globin Gene Complex: Genotype-Phenotype Correlation of 119 Cases

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3374-3374
Author(s):  
Molly Susan Hein ◽  
Jennifer L Oliveira ◽  
Kenneth C Swanson ◽  
Patrick A Lundquist ◽  
Joella A Yungerberg ◽  
...  
Keyword(s):  
Control Region ◽  
Globin Gene ◽  
Locus Control Region ◽  
Microcytic Anemia ◽  
Beta Thalassemia ◽  
Gene Complex ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Large Deletions

Abstract Background: Large deletions involving the beta globin complex are relatively rare. They can be categorized generally into five groups by deletion size and/or location: 1) beta zero thalassemia (BZT); 2) delta beta thalassemia (DBT); 3) hereditary persistence of fetal hemoglobin (HPFH); 4) gamma delta beta thalassemia (GDBT); and 5) epsilon gamma delta beta thalassemia (EGDBT). These deletions are not well understood but often have significant clinical impact, either when present alone or in combination with other hemoglobin mutations. In this study, we analyze phenotypic and molecular data on a large number of cases with deletions in the beta globin gene complex to better classify these five groups of deletions as they occur in isolation. Methods: A query of the routine clinical testing patient files from the Mayo Clinic Metabolic Hematology and Molecular Genetics Laboratories from 2010 to 2015 identified 179 patients with a deletion confirmed by a Multiplex Ligation-dependent Probe Amplification (MLPA) assay. Twenty-four probes sets were placed from the 5' locus control region (LCR) to the 3' hypersensitivity region, spanning the beta globin gene complex. Using a Luminex LX200 flow cytometer, a gene dosage ratio was calculated for each probe set using the median fluorescent intensity value collected. The size and location of the deletion and patient phenotype were compared. Results: Of the 179 total cases, the following large deletions were identified: beta gene (HBB) (n = 47), delta (HBD) through HBB (n = 105), A-gamma (HBG2) through HBB (n = 20), and locus control region (LCR) through HBB (n = 7). One case had a deletion involving the LCR epsilon with the rest of the complex left intact. A subset (n = 60) of cases had compound hemoglobin mutations that altered the phenotype. The BZT cases had relatively high Hb A2 levels and variable Hb F levels consistent with promotor region loss. The main differences between DBT and HPFH included Hb F and Hb A2 levels. GDBT cases presented with median Hb F levels higher than that observed in DBTs, normal Hb A2, and microcytic anemia. EGDBT cases had variable features according to age of the patient and Hb F level; severe microcytic anemia was observed in neonates, milder microcytic anemia in young children, and microcytosis without anemia in an adult case. The phenotypic features of 119 patients with isolated large deletions are compiled in table 1. Conclusion: In general, all five categories of large deletions in an isolated heterozygous state can present with microcytic anemia and are typically benign with the exception of transient severe microcytic anemia in neonatal EGDBT cases. Although phenotypes associated with large deletions involving the beta globin gene complex are frequently distinctive, significant phenotypic overlap can be seen in a subset of cases. These cases require molecular analysis due to their clinical importance when in combination with another beta globin gene complex mutation for an adequate diagnosis and treatment approach. Table 1. Deletion type Age n HbF (%) HbA2 (%) Hb (g/dL) MCV (fL) RBC (10^12/L) RDW (%) MCH (pg/cell) BZT 20 6.3 (0.6-94.4) 6.8 (3.4-11.6) 11.1 (8.3-14.5) 65.4 (60.8-77.2) 5.4 (4.2-6.2) 19.2 (16.6-21.2) 20.9 (18.3-25.7) DBT 56 10.6 (2.7-22.4) 2.7 (2.5-3.1) 11.7 (8.6-14.4) 68.9 (61.3-83.5) 5.3 (4.1-7.3) 21.4 (18.2-26.8) 21.6 (19.9-39.2) HPFH 23 25.9 (17.6-39.7) 2.0 (1.5-2.4) 11.6 (8.1-16.7) 78.4 (60.2-101.9) 4.4 (3.0-6.3) 17.5 (14.1-22.3) 25.4 (17.6-29.7) GDBT 14 13.3 (8.2-19.0) 2.6 (1.8-2.7) 11.0 (8.6-14.1) 72.5 (57.9-82.1) 5.1 (3.5-6.2) 20.6 (17.4-23.5) 22 (17.9-25.1) EGDBT* 28 Y 1 0.3 3 13.3 59.4 6.9 15.4 19.2 1-4 Y 3 0.9 (0-1.6) 3.2 (2.9-3.5) 9.5 (8.8-13.3) 57.8 (57.6-59.4) 5.2 (4.9-6.9) 16.6 (15.4-17.4) 18.5 (18.1-19.2) <6 month 2 21.4 (14.8-27.9) 2.6 (2.2-2.9) 6.3 (6.0-6.6) 61.3 (59.9-62.6) 3.4 (3.3-3.3) 21.5 (21.2-21.7) 18.4 (18.1-18.7) medians, (min, max); *stratified by age Disclosures No relevant conflicts of interest to declare.

scholarly journals Beta-thalassemia unlinked to the beta-globin gene in an English family

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 961-967 ◽  
Author(s):  
SL Thein ◽  
WG Wood ◽  
SN Wickramasinghe ◽  
MC Galvin
Keyword(s):  
Globin Gene ◽  
Microcytic Anemia ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Hypochromic Microcytic Anemia ◽  
Length Polymorphisms ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract An inherited hypochromic microcytic anemia transmitted in an autosomal manner has been observed in three generations of an English family. Affected members had the hallmarks of heterozygous beta-thalassemia, ie, elevated levels of hemoglobin A2 and imbalanced globin chain synthesis. However, despite extensive sequence analysis, no mutations could be found in or around the beta-globin genes of either the propositus or two other affected members from two different generations. Linkage analysis using restriction fragment length polymorphisms in the beta-globin gene cluster clearly showed that the gene responsible for the beta-thalassemia phenotype segregates independently of the beta-gene complex. Therefore, this condition represents a novel form of the disease.

scholarly journals Beta-thalassemia unlinked to the beta-globin gene in an English family

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 961-967
Author(s):  
SL Thein ◽  
WG Wood ◽  
SN Wickramasinghe ◽  
MC Galvin
Keyword(s):  
Globin Gene ◽  
Microcytic Anemia ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Hypochromic Microcytic Anemia ◽  
Length Polymorphisms ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

An inherited hypochromic microcytic anemia transmitted in an autosomal manner has been observed in three generations of an English family. Affected members had the hallmarks of heterozygous beta-thalassemia, ie, elevated levels of hemoglobin A2 and imbalanced globin chain synthesis. However, despite extensive sequence analysis, no mutations could be found in or around the beta-globin genes of either the propositus or two other affected members from two different generations. Linkage analysis using restriction fragment length polymorphisms in the beta-globin gene cluster clearly showed that the gene responsible for the beta-thalassemia phenotype segregates independently of the beta-gene complex. Therefore, this condition represents a novel form of the disease.

scholarly journals Fannin-Lubbock-I [α2β2119(GLY>ASP)], a rare mutation in the beta-globin gene, has been detected for the first time in a Hindu Brahmin family in West Bengal, India

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Jayasri Basak ◽  
Deboshree Bhattacharyya ◽  
Ashis Mukhopadhyay
Keyword(s):  
Amino Acid ◽  
West Bengal ◽  
Globin Gene ◽  
Beta Globin ◽  
Globin Chain ◽  
Rare Mutation ◽  
Direct Dna Sequencing ◽  
Beta Globin Gene ◽  
First Time ◽  
Amino Acid Glycine

AbstractThis study aims to describe the hemoglobin Fannin-Lubbock-I, which has a rare mutation substituting the amino acid glycine with aspartic acid at codon 119 of the β-globin chain. A Bengalee Hindu Brahmin family from Kolkata in West Bengal was the focus of this study. Molecular analysis using ARMS-PCR and direct DNA sequencing revealed the presence of a GGC > GAC mutation in codon 119 of the β-globin gene in a heterozygote state in three women of the same family. This is the first report of the hemoglobin Fannin-Lubbock-I from India. Our results will help to identify this mutation, which is relatively infrequent in our population.

scholarly journals A deletion/inversion rearrangement of the beta-globin gene cluster in a Turkish family with delta beta zero-thalassemia intermedia

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2455-2459
Author(s):  
AE Kulozik ◽  
A Bellan-Koch ◽  
E Kohne ◽  
E Kleihauer
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Point Mutations ◽  
Gene Promoters ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Globin Gene Cluster

The most common forms of hereditary persistence of fetal hemoglobin synthesis (HPFH) and delta beta zero-thalassemia result from simple deletions of the beta-globin gene cluster or from point mutations in the gamma-globin gene promoters. These naturally occurring mutants extend our understanding of globin gene regulation and hemoglobin switching. Furthermore, they provide the opportunity to test in vivo hypothetical switching models that are based on the experimental approach. We report here a family with delta beta zero-thalassemia from Turkey with a complex rearrangement of the beta-globin gene cluster that involves two deletions of 11.5 kb and 1.6 kb, and an inversion of 7.6 kb. The larger deletion removes both the delta-and the beta-globin genes with 3′ flanking sequences, whereas the smaller deletion affects DNA of unknown function. The inversion contains the entire L1 repeat 3′ of the beta-globin gene. There are structural motifs near the breakpoints (introduction of an “orphan” nucleotide, multiple direct and inverted repeats) suggesting a nonhomologous type of recombination event. The hematologic phenotype and the molecular structure of the rearranged beta-globin gene cluster are consistent with a competitive relationship between the fetal and the adult globin genes and/or with the translocation of enhancer sequences into the gamma-globin gene region.

scholarly journals A deletion/inversion rearrangement of the beta-globin gene cluster in a Turkish family with delta beta zero-thalassemia intermedia

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2455-2459 ◽  
Author(s):  
AE Kulozik ◽  
A Bellan-Koch ◽  
E Kohne ◽  
E Kleihauer
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Point Mutations ◽  
Gene Promoters ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Globin Gene Cluster

Abstract The most common forms of hereditary persistence of fetal hemoglobin synthesis (HPFH) and delta beta zero-thalassemia result from simple deletions of the beta-globin gene cluster or from point mutations in the gamma-globin gene promoters. These naturally occurring mutants extend our understanding of globin gene regulation and hemoglobin switching. Furthermore, they provide the opportunity to test in vivo hypothetical switching models that are based on the experimental approach. We report here a family with delta beta zero-thalassemia from Turkey with a complex rearrangement of the beta-globin gene cluster that involves two deletions of 11.5 kb and 1.6 kb, and an inversion of 7.6 kb. The larger deletion removes both the delta-and the beta-globin genes with 3′ flanking sequences, whereas the smaller deletion affects DNA of unknown function. The inversion contains the entire L1 repeat 3′ of the beta-globin gene. There are structural motifs near the breakpoints (introduction of an “orphan” nucleotide, multiple direct and inverted repeats) suggesting a nonhomologous type of recombination event. The hematologic phenotype and the molecular structure of the rearranged beta-globin gene cluster are consistent with a competitive relationship between the fetal and the adult globin genes and/or with the translocation of enhancer sequences into the gamma-globin gene region.

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