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The novel acceptor splice site mutation 11396(G→A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients

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O 1995 Oxford University Press Human Molecular Generics, 1995, Vol. 4, No. 7 1235-1237

The novel acceptor splice site mutation

11396(G+A)

in the factor XI1

gene causes a truncated transcript in cross-reacting material negative

patients

Manfred Schloesser*, Sigrun Hofferbert, Ute Bartz, Gerd ~ u t z e l , Bernhard ~ammle* and Wolfgang Engel

lnstitut fiir Humangenetik d e r Universitat Gottingen, D-37073 Gottingen. 'lnstitut fijr Klinische Chemie d e r Universitat Magdeburg, 0-39120 Magdeburg, Germany a n d 2 ~ a m a t o l o g i s c h e s Zentrallabor, Universitatsspital Bern, CH-3010 Bern, Switzerland

Received December 21. 1994; Revised a n d Accepted April 19. 1 9 9 5

Factor XI1 (Hageman factor) is an important element in several plasma protease cascades such as the blood coagulation system, the kinin system and fibrinolysis (1). Homozygous factor XI1 deficiency with no enzymatic activity is thought to result in a slightly increased risk of venous thromboembolism, but placental thrombosis, myocardial infarction and other throm- botic complications have been reported in some patients (2,3). The factor XI1 protein has the typical features of a member of the serine protease family with the active site residues encoded by the terminal exons 10-14 (4). To date only a few sequence alterations responsible for factor XI1 deficiency were found in these exons (5-8). In some patients an additional TaqI site in the second intron of the gene was detected. This TaqI site was not detected in control groups with normal factor

XI1 activities (9). We report here a novel mutation termed 11396 (G+A), a G to A transition at nucleotide position 1 1396 of the gene. ~ l o o d samples from 12 patients whose low factor XI1 activity was detected by chance during presurgery

Table 1. Genotypes and factor XI1 parameters for factor XI1 deficient patients Patient 11396 (G+A) FX1I:C F XII: Ag PTT (s)

*denotes unrelated patients from our group of 12 independent cases; 8 denotes members of the family described in the pedigree (Fig. 2). Wild type sequence (+), mutant sequence (-), FXI1:C = factor XI1 activity, F X1I:AG = factor XI1 antigen level, PTT = partial thromboplastin time, n.d. = not determined.

Table 2. Primer sequences for analysis of exons 13 and 14 as depicted in Figure 1

screening were collected. Genomic DNA was prepared and analysed by PCR and direct sequencing for mutations .as described (10). RNA preparation and cDNA synthesis with subsequent PCR was performed according to Schloesser et al. (11). Total RNA from peripheral blood lymphocytes was reverse transcribed by exon 14 specific primer and amplified in two stages with primers located in exons 11, 12 and 14 (Tables 1 and 2). For both genomic and cDNA templates PCR conditions included pairs of primers (10 pmol) in a total

Factor XIi prlmary transcript

11 3960->A

spliclng products

Wild type cDNA

--

10 11 12 13 14 Mutant cDNA p 10 11 12 13 14 + + 4 JM32 EXl2F JM35 + C EXl3F EX14R2

Figure 1. Factor XI1 primary transcripts and splicing products as derived from the analysis of transcripts. The hatched bar symbolises the truncated exon 14 sequences and the aberrant reading frame.

Figure 2. Family pedigree for patients 97-104. The mutant allele was detected in the patients with half filled squares and circles, respectively. Factor XI1 parameters are listed in Table 1.

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Figure

Table  2.  Primer  sequences  for  analysis  of  exons  13  and  14  as  depicted  in  Figure  1

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