Genetic mapping and characterization of the bleeding disorder in the fawn-hooded hypertensive rat

Yvonne H. Datta; Francisca C.Wu; Pierre C. Dumas; Artur Rangel-Filho; Milton W. Datta; Gang Ning; Brian C. Cooley; Rebecca R. Majewski; Abraham P. Provoost; Howard J. Jacob

doi:10.1055/s-0037-1613405

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 89(06): 1031-1042
DOI: 10.1055/s-0037-1613405

Platelets and Blood Cells

Schattauer GmbH

Genetic mapping and characterization of the bleeding disorder in the fawn-hooded hypertensive rat

Yvonne H. Datta

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

²Blood Research Institute, Milwaukee, Wisconsin, USA

,

Francisca C.Wu

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Pierre C. Dumas

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Artur Rangel-Filho

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Milton W. Datta

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Gang Ning

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Brian C. Cooley

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Rebecca R. Majewski

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Abraham P. Provoost

³Erasmus University, Rotterdam, The Netherlands

,

Howard J. Jacob

¹The Medical College of Wisconsin, Milwaukee, Wisconsin, USA

› Author Affiliations

Abstract

Summary

Release of platelet dense granule contents occurs in response to vascular injury, playing an important role in platelet aggregation and primary hemostasis. Abnormalities of the platelet dense granules results in a bleeding disorder of variable severity termed “storage pool defect” (SPD). We have examined the fawn-hooded hypertensive (FHH) rat as a model of SPD in order to genetically map the locus (Bd) responsible for prolonged bleeding. Platelet function assays of the FHH rat confirmed the presence of a platelet dense granule SPD. However electron microscopy and lysosomal enzyme assays indicated differences between the FHH rat and other rodent models of SPD. Genetic mapping through the use of congenic FHH rats localized the Bd locus to an approximately 1 cM region on rat chromosome 1. Through the use of comparative mapping between species and analysis of the initial draft of the rat genome assembly, six known and thirty-four putative genes were identified in the Bd locus. None of these genes have been previously implicated in platelet function. Therefore positional cloning of the gene responsible for the bleeding disorder in the FHH rat will lead to new insights in platelet physiology, with implications for diagnosis and management of hemostatic and thrombotic disorders.

Keywords

Platelets - dense granules - storage pool defect - rats - genetic mapping

Full Text

References

References
1 Hoffman R. Hematology: Basic Principles and Practice. Philadelphia: Churchill Livingstone; 2000
2 Weiss HJ, Chervenick PA, Zalusky R. Factor A: A familial defect in platelet function associated with impaired release of adeno-sine diphosphate. N Engl J Med 1969; 281: 1264-70.
3 Holmsen H, Weiss HJ. Hereditary defect in the platelet release reaction caused by a deficiency in the storage pool of platelet adenine nucleotides. Br J Haematol 1970; 19: 643-9.
4 Tschopp TB, Zucker MB. Hereditary defect in platelet function in rats. Blood 1972; 40: 217-26.
5 Raymond SL, Dodds WJ. Characterization of the fawn-hooded rat as a model for hemo-static studies. Thromb Diath Haemorrh 1975; 33: 361-9.
6 Prieur DJ, Meyers KM. Genetics of the fawn-hooded rat strain. The coat color dilution and platelet storage pool deficiency are pleiotropic effects of the autosomal recessive red-eyed dilution gene. J Hered 1984; 75: 349-52.
7 Swank RT, Novak EK, McGarry MP, Rusiniak ME, Feng L. Mouse models of Hermansky Pudlak syndrome: a review. Pigment Cell Res 1998; 11: 60-80.
8 Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking. Thromb Haemost 2001; 86: 233-45.
9 Kuijpers MH, Gruys E. Spontaneous hypertension and hypertensive renal disease in the fawn- hooded rat. Br J Exp Pathol 1984; 65: 181-90.
10 Provoost AP. Spontaneous glomerulosclerosis: insights from the fawn-hooded rat. Kidney Int 1994; (Suppl. 45) S2-S5.
11 Brown DM, van Dokkum RP, Korte MR. et al. Genetic control of susceptibility for renal damage in hypertensive fawn- hooded rats. Ren Fail 1998; 20: 407-11.
12 Brown DM, Provoost AP, Daly MJ, Lander ES, Jacob HJ. Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet 1996; 12: 44-51.
13 Cowley Jr. AW, Stoll M, Greene AS. et al. Genetically defined risk of salt sensitivity in an intercross of Brown Norway and Dahl S rats. Physiol Genomics 2000; 2: 107-15.
14 Broze Jr. GJ, Yin ZF, Lasky N. A tail vein bleeding time model and delayed bleeding in hemophiliac mice. Thromb Haemost 2001; 85: 747-8.
15 Holmsen H, Holmsen I, Bernhardsen A. Microdetermination of adenosine diphosphate and adenosine triphosphate in plasma with firefly luciferase system. Anal Biochem 1966; 17: 456-73.
16 Patil S, Newman DK, Newman PJ. Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 2001; 97: 1727-32.
17 Novak EK, Hui SW, Swank RT. Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci. Blood 1984; 63: 536-44.
18 Pujol-Moix N, Hernandez A, Escolar G, Espanol I, Martinez-Brotons F, Mateo J. Platelet ultrastructural morphometry for diagnosis of partial delta- storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases. Haematologica 2000; 85: 619-26.
19 Hui SW, Costa JL. Topography and thickness of air-dried human platelets measured by correlative transmission and scanning electron microscopy. J Microsc 1979; 115: 203-6.
20 White JG. Use of the electron microscope for diagnosis of platelet disorders. Semin Thromb Hemost 1998; 24: 163-8.
21 Glaser JH, Sly WS. Beta-glucuronidase deficiency mucopolysaccharidosis: methods for enzymatic diagnosis. J Lab Clin Med 1973; 82: 969-77.
22 Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DNA isolation procedure. Nucleic Acids Res 1991; 19: 4293
23 Kwitek AE, Tonellato PJ, Chen D. et al. Automated construction of high-density comparative maps between rat, human, and mouse. Genome Res 2001; 11: 1935-43.
24 Dell’Angelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 1999; 3: 11-21.
25 Feng L, Seymour AB, Jiang S. et al. The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky- Pudlak syndrome and night blindness. Hum Mol Genet 1999; 8: 323-30.
26 Kantheti P, Qiao X, Diaz ME. et al. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 1998; 21: 111-22.
27 Weiss HJ, Lages B, Vicic W, Tsung LY, White JG. Heterogeneous abnormalities of platelet dense granule ultrastructure in 20 patients with congenital storage pool deficiency. Br J Haematol 1993; 83: 282-95.
28 Witkop CJ, Krumwiede M, Sedano H, White JG. Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome. Am J Hematol 1987; 26: 305-11.
29 Gwynn B, Ciciotte SL, Hunter SJ. et al. Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3-independent mechanism. Blood 2000; 96: 4227-35.
30 Tobach E, DeSantis JL, Zucker MB. Platelet storage pool disease in hybrid rats. F1 fawn-hooded rats derived from crosses with their putative ancestors (Rattus norvegicus). J Hered 1984; 75: 15-8.
31 Oh J, LeCras TD, Spritz RA. Characterization and evolutionary comparison of rat Hps cDNA and exclusion of red-eyed dilution (r) locus. Mamm Genome 2001; 12: 466-8.
32 Dell’Angelica EC, Ohno H, Ooi CE, Rabinovich E, Roche KW, Bonifacino JS. AP-3: an adaptor-like protein complex with ubiquitous expression. EMBO J 1997; 16: 917-28.
33 Simpson F, Peden AA, Christopoulou L, Robinson MS. Characterization of the adaptor-related protein complex, AP-3. J Cell Biol 1997; 137: 835-45.
34 Falcon-Perez JM, Starcevic M, Gautam R, Dell’Angelica EC. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules. J Biol Chem 2002; 277: 28191-9.
35 Peters LL, Moriyama K, Huizing M. et al. Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein the is part of the palladin-muted (BLOC-1) complex. Blood 2002; 100: 125a.
36 Spritz RA. Molecular genetics of oculocutaneous albinism. Hum Mol Genet 1994; 3: 1469-75.
37 Oetting WS, King RA. Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum Mutat 1999; 13: 99-115.
38 Loftus SK, Larson DM, Baxter LL. et al. Mutation of melanosome protein RAB38 in chocolate mice. Proc Natl Acad Sci U.S.A 2002; 99: 4471-6.
39 Shirakawa R, Yoshioka A, Horiuchi H, Nishioka H, Tabuchi A, Kita T. Small GTPase Rab4 regulates Ca²⁺-induced alpha-granule secretion in platelets. J Biol Chem 2000; 275: 33844-9.
40 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-32.
41 Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104: 531-43.
42 Hall JE, Hildebrandt DA, Kuo J. Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens 2001; 14: 103S-15S.
43 Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 2001; 15: 2565-71.
44 Bernat A, Vallee E, Maffrand JP, Gordon JL. The role of platelets and ADP in experimental thrombosis induced by venous stasis in the rat. Thromb Res 1988; 52: 65-70.
45 Tiell ML, Sussman II, Moss R, Drouet LC, Spaet TH. Production of experimental arteriosclerosis in fawn-hooded rats with platelet storage pool deficiency. Artery 1982; 10: 329-40.