Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ILE865THR is now designated ILE1628THR (I1628T).
In affected members of a family with von Willebrand disease type 2A (see 613554), Iannuzzi et al. (1991) identified a 4883T-C transition in the VWF gene, resulting in an ile865-to-thr (I865T) substitution. Type 2A VWD is characterized by a qualitative defect in VWF, resulting in the absence of large and intermediate VWF multimers, which may be caused by increased VWF proteolysis. The I865T substitution was located immediately adjacent to 2 other previously identified mutations that also result in type 2A von Willebrand disease (R834W, 613160.0002 and V844D, 613160.0003), suggesting a clustering for these mutations in a portion of the protein critical for proteolysis.
Dent et al. (1990) noted that the I865T, R834W, and V844D mutations are located within a 32-amino acid segment in the midportion of the 2,813-amino acid VWF coding sequence. Type IIA von Willebrand disease is characterized by normal or only moderately decreased levels of von Willebrand factor, the absence of large and intermediate VWF multimers, and increased VWF proteolysis with an increase in the plasma levels of the 176-kD VWF proteolytic fragment. The proteolytic cleavage site is located between tyr842 and met843.
