VWD is not that uncommon of a disease and affects between 0.01 – 1% of the population, typically with type 1 being the most prevalent form (O’Brien et al. 2003). Studies have indicated that about 15% of type 1 cases have been found to have more than one possible mutation which may contribute to the disease (Yadegari et al. 2016). To determine the cause of type 1 VWD, various studies have been conducted trying to determine the genetic components that give rise to this disease. One of the most studied places for mutations is the VWF gene.
This gene was found to be at the end of the short arm of chromosome 12. It contains 52 exons that are directly encoded into the VWF protein (Veyradier et al. 2016). The protein itself is made of over 2800 amino acids. VWF is synthesized in the endothelial cells that line the insides of blood vessels and then are housed in storage vesicles (Paula D. James and Goodeve 2011). When they are needed, the proteins are secreted from the vesicles and cleaved into two pieces: the mature peptide and the propeptide. The mature peptide binds with other subunits and becomes the functional multimer that binds with factor VIII and repairs vascular damage (Paula D. James and Goodeve 2011). Researchers have linked some mutations in this gene locus to the onset of type 1 VWD.
Type 1 VWD is an inheritable disorder, but not the simplest one. It follows a dominant disorder inheritance pattern, but certain mutational effects are not always present and thus viewed as incomplete penetrant mutations (Paula D. James and Goodeve 2011). Certain studies have indicated that the majority of type 1 VWD express mutations in the VWF gene. Some have found that roughly 65% of type 1 VWD cases do in fact contain a mutation in this gene that may be related to the disease (Paula D. James and Goodeve 2011), which leaves a rather large margin of about 35% of type 1 patients that do not have any observable mutations in the VWF gene locus (D. Lillicrap 2009). So far, researchers have been able to narrow in on a few specific mutations that appear to be common amongst type 1 patients and make significant advancements understanding them.
One of the most noted mutations in the VWF gene region was a change from the tyrosine amino acid to cysteine at position 1584 in the 28th coding region of the VWF gene. This mutation was prevalent between 8-25% of the documented type 1 VWD cases in Canada and Europe (D. Lillicrap 2009). A study in the UK found that 2 of 10 families with type 1 VWD had this mutation whereas 100 unrelated healthy individuals were tested and did not have the mutation, indicating this change was in fact related to the disease (O’Brien et al. 2003). While healthy people typically have a VWF blood plasma above 0.50 IU mL-1,those with type 1 VWD are found to have VWF concentrations lower than 0.45 IU mL-1 (D. Lillicrap 2009). A correlation was found that if a patient has one copy of the Tyr1584Cys mutation, their VWF plasma levels are around 0.40 IU mL-1 while having two copies of the mutation plummets levels to about 0.20 IU mL-1 (D. Lillicrap 2009). The mutation has been found to cause cells to retain more of the protein rather releasing it into the bloodstream (O’Brien et al. 2003). In addition to this change in VWF levels, this mutation also has ties to the ABO blood type. It has been found that 1584Cys version appears to, a large majority of the time, be inherited with the “O” blood type, hence why so many with type 1 VWD have the same blood type (D. Lillicrap 2009). While this mutation is related to the secretion of VWF, there is a well-studied mutation that is linked to the clearance of the protein from the blood.
A change from the arginine amino acid to a histidine at site 1205 correlates with the abnormal rate of VWF clearance from the blood. Some consider this a subtype of type 1 VWD and named it the Vicenza variant (Paula D. James and Goodeve 2011). They determined vast clearance of the protein is occurring because healthy levels the propeptide that was cut off is still circulating in blood whereas the mature peptide has been depleted. Though this is the most popular mutation of this clearance expression, Cys1130Phe, Trp1144Gly, and Cys1149Arg mutations have been found to elicit the same effect. It appears that out of all type 1 cases, 5-10% seem to be involved in over-clearing VWF (D. Lillicrap 2009).
The genetic investigation conducted in previous years still stand true for today while some clarity was reached. In a recent French family study, 55% of the patients were found to have a mutation that matched what type of VWD they were diagnosed with (Veyradier et al. 2016). Before, it was harder to find mutations that correlated with type 1 VWD patients. This finding shows that advancements are being made in linking genetic causes to the disorder. For the type 1 patients, two-thirds of the 105 mutations reported were found to be novel mutations. About 51% of those mutations were changes in the amino acid sequence while the rest were incomplete proteins formed (Veyradier et al. 2016). This specific population showed that the majority (66%) of the VWD cases where of the type 2 variety versus only 25% being type 1 patients (Veyradier et al. 2016). This raised the question if the frequency of the types of disease was changing since various populations demonstrate type 1 is typically the most prevalent of the three types. Another modern study broadened what type of mutations can be linked to VWD. One research team found a silent mutation where a single nucleotide was changed, a cytosine to thymidine at position 7464, but encoded position 2488 glycine remained the same. This mutation led to an intron remaining in the mature VWF as opposed to being removed like normal. This event resulted a change in the protein’s conformation and impacted its ability to be secreted (Yadegari et al. 2016). Type 1 VWD is not limited to a single genetic mutation. Just as it has various mutational options, there are also various ways how these mutations manifest on a cellular level.