A Mouse Model for Human Unstable Hemoglobin Santa Ana

Overview

Journal Comp Med

Specialty General Medicine

Date 2017 Mar 18

PMID 28304246

Authors

Samantha I Miyashiro

Silvia M G Massironi

Claudia M C Mori

Carolina C Cruz

Mitika K Hagiwara

Paulo C Maiorka

Affiliations

Soon will be listed here.

Abstract

In the present study, we described the phenotype, histologic morphology, and molecular etiology of a mouse model of unstable hemoglobin Santa Ana. Hematologic evaluation of anemic mice (Anem/+) discovered after N-ethyl-N-nitrosourea mutagenesis revealed moderate anemia with intense reticulocytosis and polychromasia, followed by anisocytosis, macrocytosis, hypochromia, and intraerythrocytic inclusion and Heinz bodies. The mice also demonstrated hemoglobinuria, bilirubinemia, and erythrocytic populations with differing resistance to osmotic lysis. Splenomegaly (particularly in older mutant mice) and jaundice were apparent at necropsy. Histopathologic examination revealed dramatically increased hematopoiesis and hemosiderosis in hematopoietic organs and intracellular iron deposition in tubular renal cells. These data are characteristic of a congenital hemolytic regenerative anemia, similar to human anemias due to unstable hemoglobin. Genetic mapping assigned the affected gene to mouse chromosome 7, approximately 50 cM from the Hbb locus. The sequence of the mutant Hbb gene exhibited a T→C transversion at nucleotide 179 in Hbb-b1, leading to the substitution of proline for leucine at amino acid residue 88 and thus homologous to the genetic defect underlying Santa Ana anemia in humans.

References

OPFELL R, Lorkin P, Lehmann H . Hereditary non-spherocytic haemolytic anaemia with post-splenectomy inclusion bodies and pigmenturia caused by an unstable haemoglobin Santa Ana-beta-88 (F4) leucine--proline. J Med Genet. 1968; 5(4):292-7. PMC: 1468682. DOI: 10.1136/jmg.5.4.292. View

HUTTON J, Bishop J, Schweet R, RUSSELL E . Hemoglobin inheritance in inbred mouse strains. I. Structural differences. Proc Natl Acad Sci U S A. 1962; 48:1505-13. PMC: 220987. DOI: 10.1073/pnas.48.9.1505. View

Miyazaki A, Nakanishi T, Kishikawa M, Shimizu A, Jozaki K, Yonezawa T . The first Japanese case of Hb Santa Ana, an unstable abnormal hemoglobin, identified rapidly by electrospray ionization mass spectrometry. Intern Med. 1997; 36(5):365-70. DOI: 10.2169/internalmedicine.36.365. View

Jamsai D, Zaibak F, Vadolas J, Voullaire L, Fowler K, Gazeas S . A humanized BAC transgenic/knockout mouse model for HbE/beta-thalassemia. Genomics. 2006; 88(3):309-15. DOI: 10.1016/j.ygeno.2006.03.009. View

Massironi S, Reis B, Carneiro J, Barbosa L, Ariza C, Santos G . Inducing mutations in the mouse genome with the chemical mutagen ethylnitrosourea. Braz J Med Biol Res. 2006; 39(9):1217-26. DOI: 10.1590/s0100-879x2006000900009. View

HUTTON J, Bishop J, Schweet R, RUSSELL E . Hemoglobin inheritance in inbred mouse strains. II. Genetic studies. Proc Natl Acad Sci U S A. 1962; 48:1718-24. PMC: 221029. DOI: 10.1073/pnas.48.10.1718. View

Williamson D . The unstable haemoglobins. Blood Rev. 1993; 7(3):146-63. DOI: 10.1016/0268-960x(93)90002-l. View

Suzuki Y, Shimizu T, Sakai H, Tamaki M, Koizumi K, Kuriyama T . Model mice for Presbyterian hemoglobinopathy (Asn(beta108)-->Lys) confer hemolytic anemia with altered oxygen affinity and instability of Hb. Biochem Biophys Res Commun. 2002; 295(4):869-76. DOI: 10.1016/s0006-291x(02)00752-0. View

Nagababu E, Fabry M, Nagel R, Rifkind J . Heme degradation and oxidative stress in murine models for hemoglobinopathies: thalassemia, sickle cell disease and hemoglobin C disease. Blood Cells Mol Dis. 2008; 41(1):60-6. PMC: 2497002. DOI: 10.1016/j.bcmd.2007.12.003. View

10.

SANGER F, Nicklen S, Coulson A . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977; 74(12):5463-7. PMC: 431765. DOI: 10.1073/pnas.74.12.5463. View

11.

Tanaka Y, Kelleher Jr J, Schwartz E, Asakura T, Shelton J, Shelton J . Oxygen binding and stability properties of Hb Santa Ana (beta 88 Leu----Pro). Hemoglobin. 1985; 9(2):157-69. DOI: 10.3109/03630268508996997. View

12.

BISERTE G, GOUDEMAND M, Voisin D, Charlesworth D, Lorkin P, Lehmann H . [Instable hemoglobin during hemolytic anemia with erythrocytic inclusions and black urine. Hemoglobin found in Lille, analogous to Santa Ana beta 88 (F4) hemoglobin leucine-proline]. Nouv Rev Fr Hematol. 1970; 10(2):201-7. View

13.

Fairbanks V, OPFELL R, BURGERT Jr E . Three families with unstable hemoglobinopathies (Köln, Olmsted and Santa Ana) causing hemolytic anemia with inclusion bodies and pigmenturia. Am J Med. 1969; 46(3):344-59. DOI: 10.1016/0002-9343(69)90037-0. View

14.

Goncalves M, Sonati M, Kimura M, Arruda V, Costa F, Nechtman J . Association of Hb Santa Ana [alpha 2 beta (2)88(F4)Leu- > Pro] and Hb Porto Alegre [alpha 2 beta (2)9(A6)Ser- > Cys] in a Brazilian female. Hemoglobin. 1994; 18(3):235-9. DOI: 10.3109/03630269409043625. View

15.

Reeves P, Nielsen F, Fahey Jr G . AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. 1993; 123(11):1939-51. DOI: 10.1093/jn/123.11.1939. View

16.

Benz S, Nadanaciva S, Harris D . The alpha beta dimer-catalytic unit of the F1-ATPase. Biochem Soc Trans. 1995; 23(4):528S. DOI: 10.1042/bst023528s. View

17.

Imren S, Payen E, Westerman K, Pawliuk R, Fabry M, Eaves C . Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci U S A. 2002; 99(22):14380-5. PMC: 137892. DOI: 10.1073/pnas.212507099. View