A Common Human β Globin Splicing Mutation Modeled in Mice

Lewis, Jada; Yang, Baoli; Kim, Ronald; Sierakowska, Halina; Kole, Ryszard; Smithies, Oliver; Maeda, Nobuyo

doi:10.1182/blood.v91.6.2152

Cited by 74 publications

(33 citation statements)

References 12 publications

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“…Mouse models of a severe and a moderate form of b-thalassemia that recapitulate the erythrocyte and tissue abnormalities found in human b-thalassemia major/intermedia as well as LDL-R knockout mice are currently available and could be used to generate doubleknockout mice. 58,59 CONCLUSIONS The survey of heterozygous FH in a geographic area such as the island of Sardinia with a high frequency of b -thalassemia, due to a single mutation of the b-globin gene, has indicated that b -thalassemia has an LDLlowering effect in heterozygous FH, comparable to that obtained with prolonged treatment with moderate doses of statins. On this basis, it is likely that FH heterozygotes carrying b -thalassemia trait have some protection against coronary atherosclerosis and premature CHD as reported in normocholesterolemic individuals carrying this trait.…”

Section: Mechanisms Of Ldl-lowering Effect Of B -Thalassemia In Hetermentioning

confidence: 93%

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

Calandra

Bertolini²,

Pes³

et al. 2004

Seminars in Vascular Medicine

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Familial hypercholesterolemia (FH) is a codominant disorder due to a variety of mutations of the low-density lipoprotein (LDL) receptor gene that result in an elevation of plasma LDL-cholesterol (LDL-C). Plasma levels of LDL-C show large interindividual variation even in subjects carrying the same mutation of the LDL receptor gene. This variability may be due to genetic factors (modifier genes). Several surveys indicate that the overall contribution of common polymorphisms of modifier genes (such as the genes encoding apolipoproteins E and B) to this variability is less than 10%. In contrast, beta-thalassemia has a profound LDL-lowering effect. This was documented in FH patients identified on the island of Sardinia, in Italy, where 12% of the inhabitants are carriers of beta-thalassemia due to a single mutation (Q39X) of the beta-globin gene that abolishes the synthesis of beta-globin chain of hemoglobin (beta(o)-thalassemia). Plasma LDL-C in FH heterozygotes carrying the beta(o)-thalassemia trait is 25% lower than in noncarriers, regardless of the LDL receptor gene mutation. It is likely that this effect is due to two main mechanisms: (1) increased uptake of LDL by the bone marrow to provide cholesterol for the increased proliferation of erythroid progenitor cells and (2) increased production of inflammatory cytokines that reduce the hepatic secretion and increase the catabolism of LDL. In view of its LDL-C-lowering effect, beta-thalassemia trait may protect FH heterozygotes against premature coronary atherosclerosis.

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Section: Mechanisms Of Ldl-lowering Effect Of B -Thalassemia In Hetermentioning

confidence: 93%

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

Calandra

Bertolini²,

Pes³

et al. 2004

Seminars in Vascular Medicine

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“…Nonetheless, these SCD models have been instrumental in improving our understanding of vascular [105] and pulmonary complications [106] and for evaluating potential treatments [107]. Similarly, multiple mouse thalassaemia models, with various human mutations, are available [108–116].…”

Section: Non‐antibody‐mediated Rbc Clearancementioning

confidence: 99%

Use of mouse models to study the mechanisms and consequences of RBC clearance

et al. 2010

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Mice provide tractable animal models for studying the pathophysiology of various human disorders. This review discusses the use of mouse models for understanding red-blood-cell (RBC) clearance. These models provide important insights into the pathophysiology of various clinically relevant entities, such as autoimmune haemolytic anaemia, haemolytic transfusion reactions, other complications of RBC transfusions and immunomodulation by Rh immune globulin therapy. Mouse models of both antibody- and non-antibody-mediated RBC clearance are reviewed. Approaches for exploring unanswered questions in transfusion medicine using these models are also discussed.

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“…Both b +/IVSII-654 knockin and BKO mice had a phenotype of b-thalassemia intermedia, which was consistent with the previous report. 2,15,16 The animals were placed in polystylene shoebox cages, and acclimatized in the vivarium with room temperature of 22-25 C and humidity of~55% for 7 days under 12/12 h dark/light cycle. They were fed regular chow containing 1.0% calcium and 0.9% phosphorus, and reverse osmosis (RO) water ad libitum.…”

Section: Animalsmentioning

confidence: 99%

1,25‐Dihydroxyvitamin D₃‐induced intestinal calcium transport is impaired in β‐globin knockout thalassemic mice

Charoenphandhu

Kraidith

Teerapornpuntakit

et al. 2013

Cell Biochemistry & Function

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Besides being a common haematological disorder caused by a reduction in β-globin production, β-thalassemia has been reported to impair body calcium homeostasis, leading to massive bone loss and increased fracture risk. Here, we demonstrated that heterozygous β-globin knockout thalassemic mice had a lower rate of duodenal calcium absorption compared with the wild-type littermates, whereas the epithelial electrical parameters, including transepithelial resistance, were not affected, suggesting no change in the epithelial integrity and permeability. Daily subcutaneous injection of 1 µg kg(-1) 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] for 3 days enhanced the duodenal calcium absorption in wild-type, but not in thalassemic mice. Although β-thalassemia increased the mRNA level of divalent metal transporter-1, an iron transporter in the duodenum, it had no effect on the transcripts of ferroportin-1 or the principal calcium transporters. In conclusion, β-thalassemia impaired the 1,25(OH)2 D3 -dependent intestinal calcium absorption at the post-transcriptional level, which, in turn, contributed to the dysregulation of body calcium metabolism and β-thalassemia-induced osteopenia.

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A Common Human β Globin Splicing Mutation Modeled in Mice

Cited by 74 publications

References 12 publications

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

Use of mouse models to study the mechanisms and consequences of RBC clearance

1,25‐Dihydroxyvitamin D₃‐induced intestinal calcium transport is impaired in β‐globin knockout thalassemic mice

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A Common Human β Globin Splicing Mutation Modeled in Mice

Cited by 74 publications

References 12 publications

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

β-Thalassemia Is a Modifying Factor of the Clinical Expression of Familial Hypercholesterolemia

Use of mouse models to study the mechanisms and consequences of RBC clearance

1,25‐Dihydroxyvitamin D3‐induced intestinal calcium transport is impaired in β‐globin knockout thalassemic mice

Contact Info

Product

Resources

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1,25‐Dihydroxyvitamin D₃‐induced intestinal calcium transport is impaired in β‐globin knockout thalassemic mice