Subscribe to RSS
DOI: 10.1160/TH06-07-0417
Combined partial exon skipping and cryptic splice site activation as a new molecular mechanism for recessive type 1 von Willebrand disease
Financial support: This work was supported by grants from the Telethon Foundation and MURST (60%, 2003).Publication History
Received
31 July 2006
Accepted after resubmission
09 October 2006
Publication Date:
29 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200606/lookinside/thumbnails/10-1160-th06-07-0417-1.jpg)
Summary
We describe the complex picture associated with a mutated splice junction in intron 13 of von Willebrand factor (VWF) gene. The proband, characterized by a marked decrease in plasma and platelet VWF and near normal multimer organization, was classified as recessive type 1 von Willebrand disease (VWD). Genetic analysis demonstrated that he was homozygous for the 1534–3C>A mutation in the consensus sequence of the acceptor splicing site of intron 13 of the VWF gene. Platelet mRNA analysis documented three VWF transcripts: a wild type generated by the correct recognition of the mutated splice site, a smaller transcript not containing exon 14, and a longer one that, in addition to exons 13 and 14, included a 62bp fragment corresponding to the end of intron 13. The small transcript derives from the skipping of exon 14, the long one from the activation of a cryptic splice site in intron 13; both show a premature stop codon inVWF propeptide, so the probandVWF derives entirely from the correct splice site recognition. Combined incomplete exon skipping and cryptic splice site activation are first recognized in VWD. Since the 1534–3C>A mutation does not abolish the normal processing of mRNA, it is unlikely to be found in type 3VWD. This mutation therefore appears to be peculiar to type 1 VWD.
-
References
- 1 Sadler JE. Biochemistry and genetics of von Willebrand factor. Ann Rev Biochem 1998; 67: 395-424.
- 2 Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904.
- 3 Sadler EJ. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
- 4 Sadler JE, Mannucci PM, Berntorp E. et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160-74.
- 5 Eikenboom JC, Reitsma PH, Peerlinck KMJ. et al. Recessive inheritance of von Willebrand’s disease type 1. Lancet 1993; 341: 982-6.
- 6 Eikenboom JCJ, Matsushita T, Retsma PH. et al. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88: 2973-9.
- 7 Eikemboom JCJ, Castaman G, Vos HL. et al. Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin. Thromb Haemost 1998; 79: 709-17.
- 8 Sadler EJ. Von Willebrand disease type 1: a diagnosis in search of a disease. Blood 2003; 101: 2089-3.
- 9 Mancuso DJ, Tuley EA, Westfield LA. et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 15914-47.
- 10 Ngo KY, Glotz VT, Koziol JA. et al. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease. Proc Natl Acad Sci USA 1988; 85: 2753-7.
- 11 Zhang ZP, Falk G, Blomback M. et al. A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients. Hum Mol Genet 1992; 01: 767-8.
- 12 Eikenboom JCJ, van Amstel HKPloos, Reitsma PH. et al. Mutations in severe, type III von Willebrand’s disease in the Dutch population: candidate missense and nonsense mutations associated with reduced levels of von Willebrand factor messenger RNA. Thromb Haemost 1992; 68: 448-54.
- 13 Mertes G, Ludwig M, Finkelnburg B. et al. A G+3-to-T donor splice site mutation leads to skipping of exon 50 in von Willebrand factor mRNA. Genomics 1994; 24: 190-1.
- 14 Nichols WC, Lyons SE, Harrison JS. et al. Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment length polymorphism analysis. Proc Natl Acad Sci USA 1991; 88: 3857-61.
- 15 Casonato A, De Marco L, Mazzuccato M. et al. A new congenital platelet abnormality characterized by spontaneous platelet aggregation, enhanced von Willebrand factor platelet interaction and the presence of all von Willebrand factor multimers in plasma. Blood 1989; 74: 2028-33.
- 16 Casonato A, Fabris F, Vicariotto M. et al. The evaluation of factor VIII antigen by means of a simple slide test. Am J Clin Path 1985; 29: 309-16.
- 17 Casonato A, Pontara E, Bertomoro A. et al. von Willebrand factor collagen binding activity in the diagnosis of von Willebrand disease: an alternative to ristocetin cofactor activity?. Brit J Haematol 1999; 112: 578-83.
- 18 Gibaldi M, Perrier D. Pharmacokinetics. NewYork, NY: Marcel Dekker; 1975
- 19 Goodeve AC, Eikenboom JCJ, Ginsburg D. et al. A standard nomenclature for von Willebrand factor gene mutations and polymorphisms. Thromb Haemost 2001; 85: 929-31.
- 20 Peake IR, Liddell MB, Moodie P. et al. Severe type III von Willebrand’s disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual. Blood 1990; 75: 654-61.
- 21 Sadler JE, Rodeghiero F. on behalf of the ISTH SSC Subcommittee on von Willebrand factor. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005; 03: 775-7.
- 22 Bodo I, Katsumi A, Tuley EA. et al. Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood 2001; 98: 2973-9.
- 23 Casonato A, Pontara E, Sartorello F. et al. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99: 180-4.
- 24 Krawczak M, Reiss J, Cooper DN. The mutation spectrum of single-base pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90: 41-54.
- 25 Nakai K, Sakamoto H. Construction ofa novel database containing aberrant splicing mutations of mammalian genes. Gene 1994; 141: 171-7.
- 26 Berget SM. Exon recognition in vertebrate splicing. J Biol Chem 1995; 270: 2411-4.
- 27 Ginsburg D, Sadler JE. Von Willebrand disease: A database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-84.
- 28 Zhang ZP, Blomback M, Egberg N. et al. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics 1994; 21: 188-93.
- 29 Mikkola H, Muszbeck L, Laiho E. et al. Molecular mechanism of a mild phenotype in coagulation factor XIII (XIII) deficiency: a splicing mutation permitting partial correct splicing of XIII A-subunit mRNA. Blood 1997; 89: 1279-87.
- 30 Kaler SG, Gallo LK, Percy AK. et al. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet 1994; 08: 195-202.
- 31 Arredondo-Vega FX, Santisteban I, Kelly S. et al. Correct splicing despite mutation of the invariant first nucleotide of a 5’ splice site: A possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency. Am J Hum Genet 1994; 54: 820-30.
- 32 Tee MK, Lin D, Sugawara T. et al. T>A transversion 11 bp from a splice acceptor site in human gene for steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia. Hum Mol Genet 1995; 04: 2299-305.
- 33 Maquat LE. Nonsense-mediated RNA decay in mammalian cells: a splicing-dependent means to down-regulate the levels of mRNAs that prematurely terminate translation. In: Translational control of gene expression. Cold Spring Harbor Press, Cold Spring Harbor; New York, NY: 2000: 849-68.
- 34 Roca X, Sachidanandam R, Krainer AR. Intrinsic differences between authentic and cryptic 5’ splice sites. Nucleic Acids Res 2003; 31: 6321-33.