Molecular basis for dominantly inherited inclusion body beta-thalassemia.

Thein, Swee Lay; Hesketh, C; Taylor, Paul; Temperley, I. J.; Hutchinson, Robert; Old, John; Wood, W. G.; Clegg, J. B.; Weatherall, D. J.

doi:10.1073/pnas.87.10.3924

Cited by 171 publications

(104 citation statements)

References 19 publications

(8 reference statements)

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“…These phenotypes were associated with the triplication and quadruplication of ␣ genes, or heterozygosity for a dominant ␤-thalassemia allele. 15 The transfusion status of patients with E-␤ 0 -thalassemia did not seem to be affected by the coinheritance of ␣ mutations. Hemoglobin H-Constant Spring disorders were more likely, compared with those with hemoglobin H disease resulting from gene deletions, to require regular transfusions (33% vs 0%; P Ͻ .001) and to have undergone splenectomy (17% vs 0%; P Ͻ .01).…”

Section: Resultsmentioning

confidence: 95%

“…12,13 With the addition of the California region in 1993, Ͼ90% of the patients surveyed were within the present TCRN center regions. In the 1993 survey, the geographic locations of the 443 patients identified were Canada (116), New York (142), California (52), Northeast (44), Philadelphia (30), Chicago (15), and other (44). 14 To determine if the TCRN patient epidemiology is representative of North American patients, a survey of 87 additional clinical programs representing each region in North America was undertaken.…”

Section: Molecular and Clinical Definitionsmentioning

confidence: 99%

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Changes in the Epidemiology of Thalassemia in North America: A New Minority Disease

Vichinsky¹,

et al. 2005

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ABSTRACT. Objective. Changing patterns of immigration to North America, along with improved treatment, have altered the clinical spectrum of thalassemia, one of the world's most common genetic diseases. The new demography of the disease, with its widely variable phenotypes, has implications for its diagnosis, counseling, and management. Characterization of the new spectrum of this ancient disease, now predominated by minority groups, is essential for optimizing survival.Methods. The National Institutes of Health-sponsored North American Thalassemia Clinical Research Network (TCRN) conducted a cross-sectional study of 721 patients with thalassemia syndromes. A detailed chart review was undertaken to define the relationships between ethnic origins, genotype, and phenotype. These results were compared with 3 previous surveys of similar regions. To determine if the TCRN patient epidemiology is representative of North American patients, 87 additional programs were reviewed, and hemoglobinopathy programs from the 2 largest thalassemia regions, Ontario and California, were analyzed.Results. A total of 721 patients completed analysis in the TCRN study, including 389 (54%) patients with ␤-thalassemia major, 105 (15%) patients with ␤-thalassemia intermedia, 95 (13%) patients with hemoglobin E-␤-thalassemia, and 132 (18%) patients with ␣-thalassemia. ␤-Thalassemia predominated in Eastern North America. Hemoglobin E-␤-thalassemia and ␣-thalassemia were common on the Western continent. Genotype broadly correlated with the clinical phenotype. However, there was marked heterogeneity in clinical phenotype among patients with similar globin mutations. In ␤-thalassemia disorders, coinheritance of the ␣-thalassemia trait, triplication of ␣-thalassemia genes, and heterozygosity for the dominant ␤-thalassemia allele affected the clinical phenotype. In ␣-thalassemia disorders, structural mutations such as hemoglobin H-Constant Spring resulted in a severe hemoglobin H phenotype. Sixty percent of patients received regular transfusions, and 86% received regular iron-chelation therapy. Increased survival and decreasing birth rates of Mediterranean patients resulted in an aging Greek/Italian population being replaced by a young Asian/Middle Eastern population. Now, Asian patients account for >50% of the thalassemia population. Evidence of increasing survival is reflected in an advancing mean age of white patients with thalassemia major (25 years, up from 11 years in 1974). The results of the non-TCRN thalassemia survey confirm these observations and describe a young multiethnic thalassemia population distributed throughout North America. Newborn-screening results suggest that thalassemia births in North America are increasing and reflect the change in genotype and phenotype observed in the TCRN populations.Conclusions.

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Section: Resultsmentioning

confidence: 95%

Section: Molecular and Clinical Definitionsmentioning

confidence: 99%

Changes in the Epidemiology of Thalassemia in North America: A New Minority Disease

Vichinsky¹,

et al. 2005

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“…Patient erythrocytes typically display abnormal morphology with microcytosis, hypochromia, moderate to severe anisopoikilocytosis, basophilic stippling, and inclusions that may be become particularly prominent following splenectomy (Steinberg et al 2001). Weatherall, Thein, and colleagues characterized several hyperunstable mutations in exon 3 of the b-globin gene (Thein et al 1990). All of the mutations were frameshifts or nonsense codons that produced relatively long (.120 amino acid) proteins with carboxy-terminal truncations.…”

Section: Selected Variants That Illustrate Important Aspects Of Hemogmentioning

confidence: 99%

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

Thom

Dickson

Gell

et al. 2013

Cold Spring Harbor Perspectives in Medicine

218

182

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Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples.

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“…For instance, individuals with dominantly inherited beta-thalassemia or inclusion body betathalassemia clinically exhibit thalassemia intermedia [38,39]. These patients have moderate anemia and splenomegaly.…”

Section: Thalassemia Intermediamentioning

confidence: 99%

Understanding Beta-Thalassemia with Focus on the Indian Subcontinent and the Middle East

Lahiry¹,

Al-Attar²,

Ra³

2008

TOHJ

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Beta-thalassemia is one of the most prevalent autosomal disorders in the world. Mutations in the HBB gene underlie deficiencies in hemoglobin production, which can interfere with oxygen delivery resulting in wide range of disease severity. Although >535 mutations have been characterized in the HBB gene, beta-thalassemia is broadly classified into three groups, based on clinical severity: beta-thalassemia major, beta-thalassemia intermedia and beta-thalassemia minor. In this article we review: 1) the molecular and biochemical basis of beta-thalassemia; 2) clinical features; 3) the range of common molecular variants of beta-thalassemia in a subset of geographic regions within the Indian Subcontinent and the Middle East; 4) potential molecular diagnostics; and 5) current and future treatments. We suggest that efforts to more completely characterize the HBB mutation distribution in high-risk areas, such as the Indian Subcontinent and the Middle East, may lead to improved diagnosis with earlier and more effective intervention strategies.

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Molecular basis for dominantly inherited inclusion body beta-thalassemia.

Cited by 171 publications

References 19 publications

Changes in the Epidemiology of Thalassemia in North America: A New Minority Disease

Changes in the Epidemiology of Thalassemia in North America: A New Minority Disease

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

Understanding Beta-Thalassemia with Focus on the Indian Subcontinent and the Middle East

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