Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D9D3 and D4 domains

Erica De Candia, Massimiliano Papi, Giordano Perini, Raimondo De Cristofaro, Monica Sacco, Maira Tardugno, Leonardo Di Gennaro, Maria Basso, Mattia Ferrarese, Francesco Bernardi, Mirko Pinotti, Betti Giusti, Giancarlo Castaman

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G.A and (2) c.6532G.T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D9D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient's daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C.T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q/2178S promote conformational transitions in the VWF molecule, causing a type 2B-like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.
Lingua originaleEnglish
pagine (da-a)3405-3415
Numero di pagine11
RivistaBLOOD ADVANCES
Volume4
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • bleeding disorders
  • vonWillebrand disease

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