György Sinkovits1, Edina Szabó1, Dorottya Csuka1, Ágnes Szilágyi1, Marienn Réti2, Zoltán Prohászka1
1 Research Laboratory, 3rd Department of Internal Medicine, and MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
2 Dept. of Hematology and Stem Cell Transplantation, St. László Hospital Campus, South-Pest Hospital Center, Institute of Hematology and Infectology, Budapest, Hungary
Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, characterized by the deficiency of the ADAMTS13 protease, which is responsible for cleaving ultra-large von Willebrand factor. ADAMTS13 deficiency is caused by anti-ADAMTS13 autoantibodies in the acquired form of the disease, or by (compound heterozygous or homozygous) pathogenic mutations in its hereditary form. The pathogenic c.3178C>T (p.R1060W) mutation was described in predominantly adult-onset hereditary TTP cases, often associated with pregnancy. Interestingly, this mutation was reported to cause ADAMTS13 deficiency in heterozygous form, in the absence of other pathogenic mutations; in some of these cases, anti-ADAMTS13 antibodies were detectable.
Aims: In order to better understand the mechanism by which the c.3178C>T mutation can lead to ADAMTS13 deficiency in heterozygous form, and to investigate its association with anti-ADAMTS13 antibodies, our aim was to investigate the presence of the c.3178C>T mutation in a cohort of hereditary and acquired TTP patients in our registry, and its association with clinical parameters, other mutations, and antibody levels, if possible.
Methods: The full ADAMTS13 gene (29 exons) was sequenced in 8 hereditary TTP patients, whereas only exon 24 (containing c.3178) was sequenced in 146 acquired TTP patients, and 2 healthy relatives of a hereditary patient carrying the c.3178C>T mutation by Sanger sequencing.
Results: One (HUN994) out of the two adult-onset hereditary TTP patients in our cohort was found to carry the c.3178C>T mutation in compound heterozygous form together with the common pathogenic c.4143-4144insA mutation. No other hereditary or acquired TTP patients and none of the available relatives of HUN994 carried the c.3178C>T mutation.
Conclusion: The c.3178C>T mutation was present in one adult-onset hereditary TTP patient in our cohort. However, in contrast with previous studies, the c.3178C>T mutation was not found either in heterozygous form or in patients with detectable anti-ADAMTS13 antibodies in our cohort.
Doctoral School: Basic and Translational Medicine
Program: Vascular Pathophysiology / Atherosclerosis
Supervisor: Zoltán Prohászka
E-mail address: email@example.com