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Hb Costa Rica or α2β277(EF1)His→Arg: The first example of a somatic cell mutation in a globin gene

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Abstract

We have identified a minor hemoglobin component (∼5%) in the blood of a healthy Costa Rican female, but not in her mother and two brothers (father not studied), that has an His→Arg replacement at position β77 (Hb Costa Rica). No other amino acid replacements were observed and no β- or γ-chain-like peptides were present. Hb Costa Rica has a normal stability. Sequence analyses of numerous polymerase chain reaction (PCR)-amplified segments of DNA that contain exon 2 of the β gene failed to identify a CAC→WGC (His→Arg) mutation. The same was the case when cDNA was sequenced, indicating that a β-Costa Rica-mRNA could not be detected with this procedure. Gene mapping of genomic DNA withBglII,BamHI, andHindIII gave normal fragments only and with the same intensity as observed for the fragments of a normal control. The quantities of the β chain variants Hb JIran and Hb Fukuyama with related mutations at (β77 vary between 30% and 45% in heterozygotes, whereas that of Hb F-Kennestone with the same His→Arg mutation but in theGyγ-globin gene, is a high 40%–45% (as percentage of totalGγ) in a heterozygous newborn. These different observations exclude a heterozygosity of the A→G mutation at codon β77, as well as a deletion comparable to that of Hbs Lepore or Kenya, or a β-globin gene duplication, and point to a nontraditional inheritance of Hb Costa Rica. Allele-specific amplification of cDNA with appropriate primers identified the presence of a low level of mutated mRNA in the reticulocytes of the patient, which was confirmed by dotblot analysis of the same material with32p-labeled probes. Comparable amplification products were not observed in genomic DNA. The A→G mutation apparently occurred in a somatic cell at a relatively early stage in the development of the hematopoietic cell system, and Hb Costa Rica accumulated through rapid cell divisions in patchy areas in the bone marrow (somatic mosaicism). An unequal distribution of Hb Costa Rica over the red cells supports this possibility.

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References

  • Ali MAM, Pinkerton P, Chow SWS, Zaetz SD, Wilson JB, Webher BB, Hu H, Kutlar A, Kutlar F, Huisman THJ (1988) Some rare hemoglobin variants with altered oxygen affinities; Hb Linköping [β36(C2)Pro→Thr], Hb Caribbean [β91(F7)Leu→ Arg], and Hb Sunnybrook [β36(C2)Pro→Arg]. Hemoglobin 12:137–148

    CAS  PubMed  Google Scholar 

  • Arcasoy A, Turhanoglu I, Gozdasoglu S, Ogur G (1986) First observation of Hemoglobin J-Iran [β77(EF1)His→Asp] in Turkey. Hemoglobin 10:209–213

    CAS  PubMed  Google Scholar 

  • Austin KD, Hall JG (1992) Nontraditional inheritance. In: Hall JG (ed) The pediatric clinics of North America. (Medical genetics II, vol 39) Saunders, Philadelphia, pp 335–348

    Google Scholar 

  • Baysal E, Huisman THJ (1994) Detection of common deletional α-thalassemia-2 determinants by PCR. Am J Hematol 46:208–213

    CAS  PubMed  Google Scholar 

  • Bissé E, Wieland H (1988) High-performance liquid chromatographic separation of human haemoglobins: simultaneous quantitation of foetal and glycated haemoglobins. J Chromatogr 434:95–110

    PubMed  Google Scholar 

  • Bowden DK, Vickers MA, Higgs DR (1992) A PCR-based strategy to detect the common severe determinants of a thalassaemia. Br J Haematol 81:104–108

    CAS  PubMed  Google Scholar 

  • Chomczynski P (1993) A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 15:532–537

    CAS  PubMed  Google Scholar 

  • Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  • Divoky V, Bissé E, Wilson JB, Gu L-H, Wieland H, Heinrichs I, Prior JF, Huisman THJ (1992) Heterozygosity for the IVS-I-5 (G→C) mutation with a G→A change at codon 18 (Val→Met; Hb Baden)in cis and a T→G mutation at codon 126 (Val→Gly; Hb Dhonburi) intrans resulting in a thalassemia intermedia. Biochim Biophys Acta 1180:173–179

    CAS  PubMed  Google Scholar 

  • Efremov DG, Dimovski AJ, Huisman THJ (1994) The -158 (C→ T) promoter mutation is responsible for the increased transcription of the 3′ γ gene in the Atlanta type of hereditary persistence of fetal hemoglobin. Blood 83:3350–3355

    CAS  PubMed  Google Scholar 

  • Gonzalez-Redondo JM, Stoming TA, Lanclos K, Gu YC, Kutlar A, Kutlar F, Nakatsuji T, Deng B, Han IS, McKie VC, Huisman THJ (1988) Clinical and genetic heterogeneity in Black patients with homozygous β-thalassemia from the Southeastern United States. Blood 72:1007–1014

    CAS  PubMed  Google Scholar 

  • Gu YC, Landman H, Huisman THJ (1987) Two different quadruplicated a globin gene arrangements. Br J Haematol 66:245–250

    CAS  PubMed  Google Scholar 

  • Hall JG (1988) Somatic mosaicism: observations related to clinical genetics. Am J Hum Genet 43:355–363

    CAS  PubMed  Google Scholar 

  • Headlee ME, Gardiner MB, Reese AL, Huisman THJ (1983) The distribution of fetal hemoglobin and the types of γ chain in red cell fractions separated by gradient centrifugation from blood of patients with sickle cell anemia and other hemoglobinopathies. Biochem Med 29:337–354

    Article  CAS  PubMed  Google Scholar 

  • Hidaka K, Iuchi I, Miyake K, Nakahara H, Iwakawa G (1988) Hb Fukuyama [β77 (EFl)His→Tyr]: A new abnormal hemoglobin discovered in a Japanese. Hemoglobin 12:391–394

    CAS  PubMed  Google Scholar 

  • Huisman THJ, Jonxis JHP (1977) The hemoglobinopathies techniques of identification. (Clinical and biochemical analysis, vol 6) Dekker, New York

    Google Scholar 

  • Kutlar A, Kutlar F, Wilson JB, Headlee MG, Huisman THJ (1984) Quantitation of hemoglobin components by high performance cation-exchange liquid chromatography: its use in diagnosis and in the assessment of cellular distribution of hemoglobin variants. Am J Hematol 17:39–53

    CAS  PubMed  Google Scholar 

  • Landin B, Jeppsson J-O (1993) Rare β chain hemoglobin variants found in Swedish patients during Hb A1c analysis. Hemoglobin 17:303–318

    CAS  PubMed  Google Scholar 

  • Molchanova TP (1993) A new screening test for unstable hemoglobins usingn-butanol and red blood cells. Hemoglobin 17:81–84

    CAS  PubMed  Google Scholar 

  • Molchanova TP, Smetanina NS, Huisman THJ (1995) A second elongated, α2-globin mRNA is present in reticulocytes from normal persons and subjects with terminating codon or poly A mutations. Biochem Biophys Res Commun 214:1184–1190

    Article  CAS  PubMed  Google Scholar 

  • Nakatsuji T, Lam H, Huisman THJ (1983) Hb F-Kennestone or α2 Gγ2 (EFl)77 His→Arg observed in a Caucasian baby. Hemoglobin 7:267–270

    CAS  PubMed  Google Scholar 

  • Ojwang PJ, Nakatsuji T, Gardiner MB, Reese AL, Gilman JG, Huisman THJ (1983) Gene deletion as the molecular basis for the Kenya-Gγ-HPFH condition. Hemoglobin 7:115–123

    CAS  PubMed  Google Scholar 

  • Poncz M, Solowiejczyk D, Harpel B, Mory Y, Schwartz E, Surrey S (1982) Construction of human gene libraries from small amounts of peripheral blood: analysis of β-like globin genes. Hemoglobin 6:27–36

    CAS  PubMed  Google Scholar 

  • Postnikov YuV, Molchanova TP, Huisman THJ (1993) Allele-specific amplification for the identification of several hemoglobin variants. Hemoglobin 17:439–452

    CAS  PubMed  Google Scholar 

  • Rahbar S, Beale D, Isaacs WA, Lehmann H (1967) Abnormal haemoglobins in Iran. Observation of a new variant — haemoglobin J Iran (α2β2 77 His→Arg). Br Med J 1:674–677

    CAS  PubMed  Google Scholar 

  • Rahbar S, Bunn HF (1987) Association of hemoglobin H disease with Hb J-Iran (β77 His→Asp): impact on subunit assembly. Blood 70:1790–1791

    CAS  PubMed  Google Scholar 

  • Righetti PG, Gianazza E, Bianchi-Bosisio A, Cossu G (1986) Conventional isoelectric focusing and immobilized pH gradients for hemoglobin separation and identification. In: Huisman THJ (ed) The hemoglobinopathies. (Methods in hematology, vol 15) Churchill Livingstone, Edinburgh, pp 47–71

    Google Scholar 

  • Saiki RK, Bugawan TL, Horn GT, Mullis KB, Erlich HA (1986) Analysis of enzymatically amplified β-globin and HLA-DQα DNA with allele-specific oligonuclectide probes. Nature 324:163–167

    Article  CAS  PubMed  Google Scholar 

  • Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467

    CAS  PubMed  Google Scholar 

  • Schroeder WA, Huisman THJ (1980) The chromatography of hemoglobin. (Clinical and biochemical analysis, vol 9) Dekker, New York

    Google Scholar 

  • Shelton JB, Shelton JR, Schroeder WA (1984) High performance liquid chromatographic separation of globin chains on a largepore C4 column. J Liquid Chromatogr 7:1969–1977

    CAS  Google Scholar 

  • Smit JW, Deggeller K, Tamminga RYJ, Wilson JB, Webber BB, Huisman THJ (1991) Hb Fukuyama or α2β277(EFl)His→Tyr observed in an Indonesian female. Hemoglobin 15:313–315

    Google Scholar 

  • Wilson JB, Lam H, Pravatmuang P, Huisman THJ (1979) Separation of tryptic peptides of normal and abnormal α, β, γ, and σ hemoglobin chains by high-performance liquid chromatography. J Chromatogr 179:271–290

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. J. B. Wilson

    Present address: Hemoglobin Laboratory, Department of Medicine, Medical College of Georgia, 30912-3128, Augusta, GA, USA

Authors and Affiliations

  1. Center for Abnormal Hemoglobin Studies, University of Costa Rica, San José, Costa Rica

    W. E. Rodriguez Romero, M. Castillo, M. A. Chaves & G. F. Saenz

  2. Laboratory of Protein Chemistry, Department of Biochemistry and Molecular Biology, Medical College of Georgia, 30912-2100, Augusta, GA, USA

    L. -H. Gu, J. B. Wilson, E. Baysal, N. S. Smetanina, J. Y. Leonova & T. H. J. Huisman

Authors
  1. W. E. Rodriguez Romero
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  2. M. Castillo
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  3. M. A. Chaves
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  4. G. F. Saenz
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  5. L. -H. Gu
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  6. J. B. Wilson
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  7. E. Baysal
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  8. N. S. Smetanina
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  9. J. Y. Leonova
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  10. T. H. J. Huisman
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Rodriguez Romero, W.E., Castillo, M., Chaves, M.A. et al. Hb Costa Rica or α2β277(EF1)His→Arg: The first example of a somatic cell mutation in a globin gene. Hum Genet 97, 829–833 (1996). https://doi.org/10.1007/BF02346198

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  • DOI: https://doi.org/10.1007/BF02346198

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