Sequence variation at multiple loci influences red cell hemoglobin concentration

Peters, Luanne L.; Shavit, Jordan A.; Lambert, Amy J.; Tsaih, Shirng Wern; Li, Qian; Su, Zhiguang; Leduc, Magalie S.; Paigen, Beverly; Churchill, Gary A.; Ginsburg, David; Brugnara, Carlo

doi:10.1182/blood-2010-05-283879

Cited by 13 publications

(26 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility is that the coding mutations in the HBB genes do not directly contribute to fitness variation, but are selectively maintained due to close physical linkage with other (possibly noncoding) sites that represent the true target of balancing selection (Runck et al, 2010). This seems especially plausible since the alternative s - and d -type alleles at the two tandemly linked HBB genes are associated with differences in Hb concentration (Peters et al, 2010). Our results and those of other recent studies (Giustarini et al, 2006; Hempe et al, 2007) suggest that the adaptive significance of the two-locus β-globin polymorphism could relate specifically to allelic differences in oxidation rate (mediated by β-globin cysteine content), and may therefore revolve around a signaling function of the Hb-metHb redox couple.…”

Section: Discussionmentioning

confidence: 99%

Oxygenation properties and oxidation rates of mouse hemoglobins that differ in reactive cysteine content

Storz¹,

Weber²,

Fago³

2012

Comparative Biochemistry and Physiology Part A: Molecular &

View full text Add to dashboard Cite

House mice (genus Mus) harbor extensive allelic variation at two tandemly duplicated genes that encode the β-chain subunits of adult hemoglobin (Hb). Alternative haplotypes differ in the level of sequence divergence between the two β-globin gene duplicates: the Hbbdand Hbbphaplotypes harbor two structurally distinct β-globin genes, whereas the Hbbshaplotype harbors two β-globin duplicates that are identical in sequence. One especially salient difference between the s-type Hbs relative to the d- and p-type Hbs relates to the number of reactive β-chain cysteine residues. In addition to the highly conserved cysteine residue at β93, the d-and p-type Hbs contain an additional reactive cysteine residue at β13. To assess the functional consequences of allelic variation in β-globin cysteine content, we measured O2-binding properties and H2O2-induced oxidation rates of mono-and dicysteinyl β-Hbs from 4 different inbred strains of mice: C57BL/6J, BALB/cJ, MSM/Ms, and CAROLI/EiJ. The experiments revealed that purified Hbs from the various mouse strains did not exhibit substantial variation in O2-binding properties, but s-type Hb (which contains a single reactive β-chain cysteine residue) was far more readily oxidized to Fe3+ metHb by H2O2 than other mouse Hbs that contain two reactive β-chain cysteine residues. These results suggest that the possession of an additional reactive cysteine residue may protect against metHb formation under oxidizing conditions. The allelic differences in β-globin cysteine content could affect aspects of redox signaling and oxidative/nitrosative stress responses that are mediated by Hb-S-nitrosylation and Hb-S-glutathionylation pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Oxygenation properties and oxidation rates of mouse hemoglobins that differ in reactive cysteine content

Storz¹,

Weber²,

Fago³

2012

Comparative Biochemistry and Physiology Part A: Molecular &

View full text Add to dashboard Cite

show abstract

“…The peak marker was D7Nds1 (43.46cM). Data from the literature indicates a QTL for cell hemoglobin concentration mean (CHCM) Chcmq3 (Chr 7, 55cM) [28], and QTLs for morphological parameters of erythrocytes, Mcvq1 (32.84cM) for MCV [27] and Hemq3 (61.37cM) for HCT [16], which were mapped in this region of chromosome 7. The QTL for HGB on chromosome 16 (10.09cM) can be compared with Hgbq1(23.27cM) [27], and this locus seems to be responsible only for the functional parameters of the erythrocytes, as there is no correlation between this location and RBC or MCV.…”

mentioning

confidence: 99%

Quantitative Trait Loci Analysis for Peripheral Blood Parameters in a (BALB/cW * C57BL/6J-Mpl hlb219/J) F2 Mice

et al. 2011

View full text Add to dashboard Cite

Abstract:The genetic basis of the peripheral blood cell parameters is not fully elucidated. Thus, it is essential to research the correlation between blood cell counts levels and the genome in laboratory animals and subsequently in humans. In the present study, we examined 288 F 2 mice from a cross between BALB/cW and C57BL/6J-Mpl hlb219 /J. The C57BL/6J-Mpl hlb219 /J strain is a mouse model of thrombocytopenia. We found very strong correlations for PLT counts and revealed some highly significant correlations for RBC counts. On the basis of the obtained results, we presume that genetic control of erythrocyte parameters is divided into two pathways: first, the morphological determinants responsible for the red blood cell count (RBC), hematocrit (HCT), and mean corpuscular volume (MCV), and second, the functional pathway determining the hemoglobin content (HGB). The locus on Chromosome 4 is the only detected quantitative trait locus (QTL) influencing the analyzed platelets parameters. We also detected highly significant correlations for erythrocyte parameters on Chromosome 1 (RBC, MCV, MCH), Chr 7 (HGB), Chr 9 (MCHC), Chr 11 (RBC), and Chr 17 (MCH). Finally, with regards to the given correlations, using the Mouse Genome Database resource, we proposed candidate genes with possible meaning for the level of these parameters: cytokine receptor genes (e.g., Mpl), transcription factor genes (e.g., Xbp1, Ikzf1), hemoglobin chain genes (e.g., , and many others localized in the confidence intervals of found QTLs.

show abstract

“…We recently identified several QTL associated with cell hydration and variations in cell hemoglobin concentration (30). Presence of the hemoglobin diffuse type (Hbb d ), which exhibits an increased net positive charge compared with the hemoglobin single (Hbb s ) type, was associated with dehydration and increased CHCM (32). Cyclin D3 has been shown to regulate erythrocyte size by affecting the number of cell divisions during the terminal differentiation of erythroid precursors (38).…”

Section: Discussionmentioning

confidence: 99%

“…The modulation of K ϩ transport by oxidant damage observed in human ␤-thalassemic erythrocytes is also observed in ␤-thalassemic mouse erythrocytes: this has allowed the in vivo study in mice of potential antioxidant compounds as candidate therapies for sickle cell anemia and thalassemia (18,29). Mouse erythrocytes have been instrumental in demonstrating that K ϩ content and transport via KCC can be modulated by the presence of mutant hemoglobins of relatively positive charge (32,37).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Strain-specific variations in cation content and transport in mouse erythrocytes

Rivera

Zee

Alper

et al. 2013

Physiological Genomics

Self Cite

View full text Add to dashboard Cite

Rivera A, Zee RY, Alper SL, Peters LL, Brugnara C. Strainspecific variations in cation content and transport in mouse erythrocytes. Physiol Genomics 45: 343-350, 2013. First published March 12, 2013 doi:10.1152/physiolgenomics.00143.2012.-Studies of ion transport pathophysiology in hematological disorders and tests of possible new therapeutic agents for these disorders have been carried out in various mouse models because of close functional similarities between mouse and human red cells. We have explored strain-specific differences in erythrocyte membrane physiology in 10 inbred mouse strains by determining erythrocyte contents of Na ϩ , K ϩ , and Mg 2ϩ , and erythrocyte transport of ions via the ouabain-sensitive Na-K pump, the amiloride-sensitive Na-H exchanger (NHE1), the volume and chloride-dependent K-Cl cotransporter (KCC), and the charybdotoxin-sensitive Gardos channel (KCNN4). Our data reveal substantial strain-specific and sex-specific differences in both ion content and trans-membrane ion transport in mouse erythrocytes. These differences demonstrate the feasibility of identifying specific quantitative trait loci for erythroid ion transport and content in genetically standardized inbred mouse strains. membrane transport; NHE1; KCNN4; KCC; Na-K pump MOUSE ERYTHROCYTES HAVE PLAYED a crucial role in the elucidation of the pathophysiology of ion transport abnormalities in human hematological diseases based on their close similarity with human erythrocytes (1). Studies on the K ϩ transportmediated by K-Cl cotransport (KCC) in mouse erythrocytes have been particularly relevant for hematological diseases characterized by red cell dehydration, such as sickle cell anemia and thalassemias (1,8,13). Mouse KCC has a high degree of homology with the human KCC (11,42), is upregulated in several mouse models of hematological diseases and shares with human KCC sensitivity to changes in erythrocyte Mg 2ϩ content and oxidant damage (2,(12)(13)(14)(15)35). The modulation of K ϩ transport by oxidant damage observed in human ␤-thalassemic erythrocytes is also observed in ␤-thalassemic mouse erythrocytes: this has allowed the in vivo study in mice of potential antioxidant compounds as candidate therapies for sickle cell anemia and thalassemia (18,29). Mouse erythrocytes have been instrumental in demonstrating that K ϩ content and transport via KCC can be modulated by the presence of mutant hemoglobins of relatively positive charge (32, 37).The Ca 2ϩ -activated K ϩ channel of human erythrocytes (KCNN4 or Gardos channel) plays an important role in the dehydration of both human and mouse sickle erythrocytes and is sensitive to charybdotoxin (ChTX) and imidazole drugs (5,34,36,41). Studies in mouse erythrocytes have also shown close structural and functional similarities between human and mouse KCNN4, demonstrating a protective role of the Gardos channel against hemolysis of both normal and spherocytic erythrocytes (17,23,45).Active transport of Na ϩ and K ϩ via the Na-K pump is responsible for the low Na ϩ /high K ϩ content ...

show abstract

Sequence variation at multiple loci influences red cell hemoglobin concentration

Cited by 13 publications

References 46 publications

Oxygenation properties and oxidation rates of mouse hemoglobins that differ in reactive cysteine content

Oxygenation properties and oxidation rates of mouse hemoglobins that differ in reactive cysteine content

Quantitative Trait Loci Analysis for Peripheral Blood Parameters in a (BALB/cW * C57BL/6J-Mpl hlb219/J) F2 Mice

Strain-specific variations in cation content and transport in mouse erythrocytes

Contact Info

Product

Resources

About