Mutations in coagulation factor XIII A gene in eight unrelated Indians

Giridhara R. Jayandharan; Auro Viswabandya; Shoma Baidya; Sukesh C. Nair; Biju George; Vikram Mathews; Mammen Chandy; Alok Srivastava

doi:10.1160/TH05-09-0617

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(03): 551-556
DOI: 10.1160/TH05-09-0617

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Mutations in coagulation factor XIII A gene in eight unrelated Indians

Five novel mutations identified by a novel PCR-CSGE approach

Authors

Giridhara R. Jayandharan

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Auro Viswabandya

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Shoma Baidya

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Sukesh C. Nair

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Biju George

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Vikram Mathews

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Mammen Chandy

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India
Alok Srivastava

¹Departments of Hematology and Clinical Pathology*, Christian Medical College, Vellore, India

Abstract

Summary

Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T>G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C>T transition predicting a Ser263Phe in the core domain and a novel c.2045–1G>A transition at the acceptor splice junction of in tron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base ‘G’ duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base ‘A’ duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations.

Keywords

Factor XIII - mutation - CSGE

Full Text

References

References
1 Lorand L. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J Thromb Haemost 2005; 03: 1337-48.
2 Lorand L, Losowsky MS, Miloszewski KJ. Human factor XIII: fibrin-stabilizing factor. Prog Hemost Thromb 1980; 05: 245-90.
3 Schwartz ML, Pizzo SV, Hill RL. et al. The subunit structures of human plasma and platelet factor XIII (fibrin-stabilizing factor). J Biol Chem 1971; 246: 5851-4.
4 Board PG, Webb GC, McKee J. et al. Localization of the coagulation factor XIII A subunit gene (F13A) to chromosome bands 6p24-p25. Cytogenetics and Cell Genetics 1988; 48: 25-7.
5 Bottenus RE, Ichinose A, Davie EW. Nucleotide sequence of the gene for the b subunit of human factor XIII. Biochemistry 1990; 29: 11195-209.
6 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104: 1243-52.
7 Anwar R, Miloszewski KJA. Factor XIII deficiency. Br J Haematol 1999; 107: 468-84.
8 Peyvandi F, Duga S, Akhavan S. et al. Rare coagulation deficiencies. Haemophilia 2002; 08: 308-21.
9 Patel AP, Chandy M, Raghupathy P. et al. Hereditary factor XIII deficiency. Indian J Pediatr 1993; 60: 441-4.
10 Williams IJ, Abuzenadah A, Winship PR. et al. Precise carrier and prenatal diagnosis in families with haemophilia A: Use of conformation sensitive gel electrophoresis for rapid mutation screening and polymorphism analysis. Thromb Haemost 1998; 79: 723-6.
11 Ichinose A, Davie EW. Characterization of the gene for the A subunit of human factor XIII (plasma transglutaminase), a blood coagulation factor. Proc of Natl Acad of Sci USA 1988; 85: 5829-33.
12 Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparitive protein modeling. Electrophoresis 1997; 18: 2714-23.
13 Anwar R, Gallivan L, Miloszewski KJ. et al. Factor XIII deficiency causing mutation, Ser295Arg, in exon 7 of the factor XIIIA gene. Thromb Haemost 2000; 84: 591-4.
14 Izumi T, Nagaoka U, Saito T. et al. Novel deletion and insertion mutations cause splicing defects, leading to severe reduction in mRNA levels of the A subunit in severe factor XIII deficiency. Thromb Haemost 1998; 79: 479-85.
15 Vysokovsky A, Saxena R, Landau M. et al. Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families. J Thromb Haemost 2004; 02: 1790-7.
16 Yamanoshita O, Kubota T, Hou J. et al. DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues. Int J Cancer 2005; 114: 74-9.
17 Jayandharan G, Shaji RV, Chandy M. et al. Identification of factor IX gene defects using a multiplex PCR and CSGE strategy- A first report. J Thromb Haemost 2003; 01: 2051-4.
18 Jayandharan G, Viswabandya A, Baidya S. et al. Six novel mutations including triple heterozygosity for Phe31Ser, 514delT and 516T-->G factor X gene mutations are responsible for congenital factor X deficiency in patients of Nepali and Indian origin. J Thromb Haemost 2005; 03: 1446-53.
19 Vianello F, Lombardi AM, Dal Bello F. et al. Conformation sensitive gel electrophoresis for detection of factor X gene mutations. Thromb Res 2002; 107: 51-4.
20 Birben E, Oner R, Oner C. et al. Mutations in coagulation factor XIII A gene in three Turkish patients: two novel mutations and a known insertion. Br J Haematol 2002; 118: 278-81.
21 Niiya T, Osawa H, Bando S. et al. A complete deficiency of factor XIII A-subunit due to a novel compound heterozygote of Ser 413 Leu missense and an nt 389 (ins G) frameshift mutation. Br J Haematol 1999; 107: 772-5.
22 Smith CWJ, Porro EB, Patten JG. et al. Scanning from an independently defined branch point defines the 3’splice site of mammalian introns. Nature 1989; 342: 243-7.
23 Tomiyama Y, Kashiwagi H, Kosugi S. et al. Abnormal processing of the glycoprotein IIb transcript due to a nonsense mutation in exon 17 associated with Glanzmann’s thrombasthenia. Thromb Haemost 1995; 73: 756-62.
24 Kangsadalampai S, Chelvanayagam G, Baker R. et al. Identification and characterization of two missense mutations causing factor XIIIA deficiency. Br J Haematol 1999; 104: 37-43.
25 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55: 127-44.
26 Aslam S, Yee VC, Narayanan S. et al. Structural analysis of a missense mutation (Val 414 Phe) in the catalytic core domain of the factor XIII(A) subunit. Br J Haematol 1997; 98: 346-52.