Aberrant Splicing and Premature Termination of Transcription of the FVIII Gene as a Cause of Severe Canine Hemophilia A: Similarities with the Intron 22 Inversion Mutation in Human Hemophilia

Christine Hough; Seiki Kamisue; Cherie Cameron; Colleen Notley; Shawn Tinlin; Alan Giles; David Lillicrap

doi:10.1055/s-0037-1613063

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 87(04): 659-665
DOI: 10.1055/s-0037-1613063

Review Article

Schattauer GmbH

Aberrant Splicing and Premature Termination of Transcription of the FVIII Gene as a Cause of Severe Canine Hemophilia A: Similarities with the Intron 22 Inversion Mutation in Human Hemophilia

Christine Hough

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

Seiki Kamisue

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

Cherie Cameron

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

Colleen Notley

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

Shawn Tinlin

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

Alan Giles

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

,

David Lillicrap

¹The Department of Pathology, Queen’s University, Kingston, Ontario, Canada

› Institutsangaben

Abstract

Summary

We have identified the causative mutation in the hemophilia A dog colony at Queen’s University, Canada and have observed a striking similarity with the intron 22 inversion found in ∼45% of severely affected hemophilia A patients. The canine hemophilia A phenotype arises from aberrant splicing and premature termination of transcription of the FVIII gene, resulting in a polyadenylated transcript lacking exons distal to 22 and terminating with a novel sequence element (NSE). In dogs and other species including humans, this NSE is present in low copy number. One copy of these sequences in the canine genome is within intron 22 and reveals differences in the hybridization banding patterns between normal and hemophilic DNA, suggestive of a large genomic rearrangement. The mutation mechanism may not be uncommon, as identical mutant transcripts were isolated from two hemophilia A littermates that are unrelated to the Queen’s colony and from hemophiliac dogs in the colony at Chapel Hill.

Keywords

Hemophilia - mutation - splicing

Volltext

Referenzen

References
1 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM. Characterization of the human factor VIII gene. Nature 1984; 312: 326-30.
2 Kemball-Cook G, Tuddenham EG, Wacey AI. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4. Nucleic Acids Res 1998; 26: 216-9.
3 Naylor JA, Green PM, Rizza CR, Giannelli F. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet 1993; 02: 11-7.
4 Goodeve AC, Preston FE, Peake IR. Factor VIII gene rearrangements in patients with severe haemophilia A. Lancet 1994; 343: 329-30.
5 Lakich D, Kazazian HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 05: 236-41.
6 Naylor JA, Buck D, Green P, Williamson H, Bentley D, Giannelli F. Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum Mol Genet 1995; 04: 1217-24.
7 Levinson B, Kenwrick S, Gamel P, Fisher K, Gitschier J. Evidence for a third transcript from the human factor VIII gene. Genomics 1992; 14: 585-9.
8 Naylor J, Brinke A, Hassock S, Green PM, Giannelli F. Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Hum Mol Genet 1993; 02: 1773-8.
9 Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J. A transcribed gene in an intron of the human factor VIII gene. Genomics 1990; 07: 1-11.
10 Mills JN, Bolton JR. Haemophilia A in a 3-year-old thoroughbred horse. Aust Vet J 1983; 60: 63-4.
11 Healy PJ, Sewell CA, Exner T, Morton AG, Adams BS. Haemophilia in Hereford cattle: factor VIII deficiency. Aust Vet J 1984; 61: 132-3.
12 Neuenschwander S, Kissling-Albrecht L, Heiniger J, Backfisch W, Stranzinger G, Pliska V. Inherited defect of blood clotting factor VIII (haemophilia A) in sheep. Thromb Haemost 1992; 68: 618-20.
13 Cotter SM, Brenner RM, Dodds WJ. Hemophilia A in three unrelated cats. J Am Vet Med Assoc 1978; 172: 166-8.
14 Brinkhous KM. Animal models of hemophilia. In: Animal models of thrombosis and hemorrhagic diseases NIH. Bethesda: 1976 WH 312 W926a 1975, 1976: 3-13.
15 Parry BW, Howard MA, Mansell PD, Holloway SA. Haemophilia A in German shepherd dogs. Aust Vet J 1988; 65: 276-9.
16 Slappendel RJ. Hemophilia A and hemophilia B in a family of French bulldogs. Tijdschr Diergeneeskd 1975; 100: 1075-88.
17 Benn DM, Gentry PA, Johnstone IB. Classic hemophilia (hemophilia A) in a family of collies. Can Vet J 1978; 19: 221-5.
18 Giles AR, Tinlin S, Greenwood R. A canine model of hemophilic (factor VIII:C deficiency) bleeding. Blood 1982; 60: 727-30.
19 Giles AR, Tinlin S, Hoogendoorn H, Greenwood P, Greenwood R. Development of factor VIII:C antibodies in dogs with hemophilia A (factor VIII:C deficiency). Blood 1984; 63: 451-6.
20 Tinlin S, Webster S, Giles AR. The development of homologous (canine/ anti-canine) antibodies in dogs with haemophilia A (factor VIII deficiency): a ten-year longitudinal study. Thromb Haemost 1993; 69: 21-4.
21 Giles AR, Tinlin S, Hoogendoorn H, Fournel MA, Ng P, Pancham N. In vivo characterization of recombinant factor VIII in a canine model of hemophilia A (factor VIII deficiency). Blood 1988; 72: 335-9.
22 Pittman DD, Alderman EM, Tomkinson KN, Wang JH, Giles AR, Kaufman RJ. Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII. Blood 1993; 81: 2925-35.
23 Mertens K, Briet E, Giles AR. The role of factor VII in haemostasis: infusion studies of factor VIIa in a canine model of factor VIII deficiency. Thromb Haemost 1990; 64: 138-44.
24 Giles AR. Functional, biochemical, and morphological evaluations of experimental hemophilia therapies in animal models. Semin Hematol 1994; 31: 56-9.
25 Gallo-Penn AM, Shirley PS, Andrews JL, Tinlin S, Webster S, Cameron C, Hough C, Notley C, Lillicrap D, Kaleko M, Connelly S. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood 2001; 97: 107-13.
26 Monahan PE, Samulski RJ, Tazelaar J, Xiao X, Nichols TC, Bellinger DA, Read MS, Walsh CE. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther 1998; 05: 40-9.
27 Girma JP, Fressinaud E, Houllier A, Laurian Y, Amiral J, Meyer D. Assay of factor VIII antigen (VIII:CAg) in 294 haemophilia A patients by a new commercial ELISA using monoclonal antibodies. Haemophilia 1998; 04: 98-103.
28 Lahiri DK, Nurnberger JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.
29 Cameron C, Notley C, Hoyle S, McGlynn L, Hough C, Kamisue S, Giles A, Lillicrap D. The canine factor VIII cDNA and 5’ flanking sequence. Thromb Haemost 1998; 79: 317-22.
30 Nichols TC, Bellinger DA, Reddick RL, Smith SV, Koch GG, Davis K, Sigman J, Brinkhous KM, Griggs TR, Read MS. The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A. Blood 1993; 81: 2644-51.
31 Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single basepair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90: 41-54.
32 Berget SM. Exon recognition in vertebrate splicing. J Biol Chem 1995; 270: 2411-4.
33 Bagnall RD, Waseem NH, Green PM, Colvin B, Lee C, Giannelli F. Creation of a novel donor splice site in intron 1 of the factor VIII gene leads to activation of a 191 bp cryptic exon in two haemophilia A patients. Br J Haematol 1999; 107: 766-71.
34 Liu X, Mertz JE. Polyadenylation site selection cannot occur in vivo after excision of the 3’-terminal intron. Nucleic Acids Res 1993; 21: 5256-63.
35 Cooke C, Hans H, Alwine JC. Utilization of splicing elements and polyadenylation signal elements in the coupling of polyadenylation and last-intron removal. Mol Cell Biol 1999; 19: 4971-9.
36 Niwa M, Berget SM. Polyadenylation precedes splicing in vitro. Gene Expr 1991; 01: 5-14.
37 Mansfield SG, Kole J, Puttaraju M, Yang CC, Garcia-Blanco MA, Cohn JA, Mitchell LG. Repair of CFTR mRNA by spliceosome-mediated RNA trans-splicing. Gene Ther 2000; 07: 1885-95.