Novel Deletion and Insertion Mutations Cause Splicing Defects, Leading to Severe Reduction in mRNA Levels of the A Subunit in Severe Factor XIII Deficiency

Tomonori Izumi; Utako Nagaoka; Tetsuo Saito; Junki Takamatsu; Hidehiko Saito; Akitada Ichinose

doi:10.1055/s-0037-1614929

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(03): 479-485
DOI: 10.1055/s-0037-1614929

Review Articles

Schattauer GmbH

Novel Deletion and Insertion Mutations Cause Splicing Defects, Leading to Severe Reduction in mRNA Levels of the A Subunit in Severe Factor XIII Deficiency

Tomonori Izumi

¹Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Yamagata, Japan

,

Utako Nagaoka

¹Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Yamagata, Japan

,

Tetsuo Saito

¹Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Yamagata, Japan

,

Junki Takamatsu

¹Department of Medicine I, Nagoya University School of Medicine, Nagoya, Japan

,

Hidehiko Saito

¹Department of Medicine I, Nagoya University School of Medicine, Nagoya, Japan

,

Akitada Ichinose

¹Department of Molecular Patho-Biochemistry, Yamagata University School of Medicine, Yamagata, Japan

› Author Affiliations

Abstract

Summary

In order to explore molecular mechanisms for factor XIII deficiency, a patient (Nagoya I) was examined at the DNA and RNA levels. Nucleotide sequence analysis of the patient’s DNA amplified by PCR revealed that he had a 20 bp deletion at the boundary of exon I/intron A, and an insertion of T in the invariant GT dinucleotide at the splicing donor site of exon IV/intron D. The presence of these heterozygous mutations was confirmed by restriction digestion of the amplified fragments of the proband and his parents. RT-PCR analysis demonstrated that only one kind of mRNA without exon IV was detected in Nagoya I, although its level was greatly reduced to less than 5% of normal. The other defective allele of the A subunit gene containing the 20 bp deletion was not detected. Thus, both mutations impaired normal processing of mRNA for the A subunit, resulting in his severe factor XIII deficiency.

Full Text

References

References
1 Folk JE, Chung SI. Blood coagulation factor XIII: Relationship of some biological properties to subunit structure.. In: Proteases and biological control.. Reich E, Rifkin DB, Shaw E. (eds). New York, NY: Cold Spring Harbor Laboratory; 1975. pp 157-70.
2 Lorand L, Losowsky MS, Miloszewski KJM. Human factor XIII. Fibrin-stabilizing factor.. Prog Thromb Hemostas 1980; 5: 245-90.
3 Ichinose A. Physiology and biochemistry of factor XIII.. In: Haemostasis and Thrombosis.. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. (eds). Edinburgh, United Kingdom: Churchill Livingstone; 1995. pp 531-46.
4 Ichinose A, Hendrickson LE, Fujikawa K, Davie EW. Amino acid sequence of the A subunit of human factor XIII.. Biochemistry 1986; 25: 6900-6.
5 Ichinose A, McMullen BA, Fujikawa K, Davie EW. Amino acid sequence of the B subunit of human factor XIII, a protein composed of ten repetitive segments.. Biochemistry 1986; 25: 4633-8.
6 Ichinose A, Bottenus RE, Davie EW. Structure of transglutaminases.. J Biol Chem 1990; 265: 13411-4.
7 Ichinose A, Davie EW. Characterization of the gene for the A subunit of human factor XIII (plasma transglutaminase), a blood coagulation factor.. Proc Natl Acad Sci USA 1988; 85: 5829-33.
8 Bottenus RE, Ichinose A, Davie EW. Nucleotide sequence of the gene for the B subunit of human factor XIII.. Biochemistry 1990; 29: 11195-209.
9 Ichinose A, Kaetsu H. Molecular approach to the structure-function relationship of human coagulation factor XIII.. Method Enzymol 1993; 222: 36-51.
10 Girolami A, Burul A, Fabris F, Cappellato G, Betterle C. Studies on factor XIII antigen in congenital factor XIII deficiency. A tentative classification of the disease in two groups.. Folia Haematol 1978; 105: 131-41.
11 Ichinose A, Izumi T, Hashiguchi T. The normal and abnormal genes of the A and B subunits in coagulation factor XIII.. Semin Thromb Haemost 1996; 22: 385-91.
12 Izumi T, Hashiguchi T, Castaman G, Tosetto A, Rodeghiero F, Girolami A, Ichinose A. Type I factor XIII deficiency is caused by a genetic defect of its B subunit: Insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain.. Blood 1996; 7: 2769-74.
13 Saito M, Asakura H, Yoshida T, Ito K, Okafuji K, Yoshida T, Matsuda T. A familial factor XIII subunit B deficiency.. Brit J Haematol 1990; 74: 290-4.
14 Hashiguchi T, Saito M, Morishita E, Matsuda T, Ichinose A. Two genetic defects in a patient with complete deficiency of the B subunit for factor XIII.. Blood 1993; 82: 145-50.
15 Hashiguchi T, Ichinose A. Molecular and cellular basis of deficiency of the B subunit for factor XIII secondary to a Cys430-Phe mutation in the seventh Sushi domain.. J Clin Invest 1995; 95: 1002-8.
16 Kamura T, Okamura T, Murakawa M, Tsuda H, Teshima T, Shibuya T, Harada M, Niho Y. Deficiency of coagulation factor XIII A subunit caused by the dinucleotide deletion at the 5’ end of exon III.. J Clin Invest 1992; 90: 315-9.
17 Board P, Coggan M, Miloszewski K. Identification of a point mutation in factor XIII A subunit deficiency.. Blood 1992; 80: 937-41.
18 Standen GR, Bowen DJ. Factor XIII aBristol 1: detection of a nonsense mutation (Arg¹⁷¹-stop codon) in factor XIII A subunit deficiency.. Br J Haematol 1993; 85: 769-72.
19 Mikkola H, Syrjala M, Rasi V, Vahtere E, Hamalainen E, Peltonen L, Palotie A. Deficiency in the A-subunit of coagulation factor XIII: Two novel point mutations demonstrate different effects on transcript levels.. Blood 1994; 84: 517-25.
20 Vreken P, Niessen RWLM, Peters M, Schaap MCL, Zuithoff-Rijntijes JGM, Sturk A. A point mutation in an invariant splice acceptor site results in a decreased mRNA level in a patient with severe coagulation factor XIII subunit A deficiency.. Thromb Haemost 1995; 74: 584-9.
21 Aslam S, Poon M-C, Yee VC, Bowen DJ, Standen GR. Factor XIII_A Calgary: a candidate missense mutation (Leu667Pro) in the beta barrel 2 domain of the factor XIII_A subunit.. Brit J Haematol 1995; 91: 452-7.
22 Coggan M, Baker R, Miloszewski K, Woodfield G, Board P. Mutations causing coagulation factor XIII subunit A deficiency: Characterization of the mutant proteins after expression in yeast.. Blood 1995; 85: 2455-60.
23 Mikkola H, Yee VC, Syrjala M, Seitz R, Egbring R, Petrini P, Ljung R, Ingerslev J, Teller DC, Peltonen L, Palotie A. Four novel mutations in deficiency of coagulation factor XIII: Consequence of expression and structure of the A-subunit.. Blood 1996; 87: 141-51.
24 Kangsadalampai S, Forges-Berth A, Caglayan SH, Board PG. New mutations causing the premature termination of translation in the A subunit gene of coagulation factor XIII.. Thromb Haemost 1996; 76: 139-42.
25 Kaetsu H, Hashiguchi T, Foster D, Ichinose A. Expression of the A and B subunits for human coagulation factor XIII in baby hamster kidney (BHK) cells: Release of the recombinant A subunit of factor XIII independent of the classical secretory pathway.. J Biochem 1996; 119: 961-9.
26 Koie K, Ogata K, Ishiguro J, Kamiya T, Asai K. Congenital factor XIII (fibrin stabilizing factor) deficiency: Report of two unrelated cases with episodes of intracranial bleeding.. Jap J Clin Hematol 1978; 19: 836-43.
27 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase.. Science 1988; 239: 487-91.
28 Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reactions.. Genomics 1989; 5: 874-9.
29 Senapathy P, Shapiro MB, Harris NL. Splice junctions, branch point sites, and exons: Sequence statistics, identification, and applications to genome project.. Method Enzymol 1990; 183: 252-78.
30 Bordonaro M, Nordstrom JL. Different mechanisms are responsible for the low accumulation of transcripts from intronless and 3’splice site deleted genes.. Biochem Biophys Res Commun 1994; 203: 128-32.
31 Yee VC, Pedersen LC, Trong IL, Bishop PD, Stenkamp RE, Teller DC. Three-dimensional structure of a transglutaminase: Human blood coagulation factor XIII.. Proc Natl Acad Sci USA 1994; 91: 7296-300.
32 Anwar R, Stewart AD, Miloszewski KJA, Losowsky MS, Markham AF. Molecular basis of inherited factor XIII deficiency: Identification of multiple mutations provides insights into protein function.. Br J Haematol 1995; 91: 728-35.
33 Watanabe A, Tanaka K, Shimura Y. The role of exon sequences in splice site selection.. Genes Dev 1992; 7: 407-18.
34 Tokunaga F, Muta T, Iwanaga S, Ichinose A, Davie EW, Kuma K, Miyata T. Limulus hemocyte transglutaminase: cDNA cloning, amino acid sequence, and tissue localization.. J Biol Chem 1993; 268: 262-8.