Abstract Number: PB1452
Meeting: ISTH 2020 Congress
Background: Inherited thrombocytopenia (IT) is a group of rare genetic disorders characterized by reduced platelet count associated to variable bleeding tendency and/or other clinical defects. Next Generation Sequencing (NGS) led to the identification of novel forms of IT and so far variants in over 30 different genes are known to cause IT that account for approximately 50% of patients suggesting that novel forms have yet to be identified.
Monoallelic variants in MECOM were recently associated with an IT called MECOM-associated syndrome and currently only three mutations have been evaluated through functional analysis.
Aims: Due to the uncertain significance of missense variants in functional domains of transcription factors we aim to investigate the functional effect of a novel variant in MECOM.
Methods: Mutational screening was performed using NGS panel. As described by literature we performed a luciferase reporter assay to test the transcriptional activity of identified variant on AP1 promoter, an indirect target of MECOM, in two different cell lines.
Results: We identified a monoallelic missense variant in MECOM (c.1901 C>T; p.P634L) in a patient with Congenital AMegakaryocytic Thrombocytopenia (CAMT). The variant identified is located in the Repression Domain and didn’t affect the Zinc Finger 8 (ZF8) where all the previously known variants are reported. We showed that the transcriptional activity of p.P634L was significantly different from that of Wild Type form in both DAMI and HEK cell lines.
Conclusions: p.P634L is overall the fourth missense MECOM variant evaluated through functional studies. We showed that not only mutations hitting the ZF8 domain might cause CAMT. The observed alteration in the transcriptional activity of p.P634L was opposite between the cell lines highlighting the strong influence of the cell context in indirect reporter assays. For this reason a new, direct assay should be developed to analyze the functional effect of MECOM missense variants.
To cite this abstract in AMA style:Papa N, Marzollo A, Faleschini M, Giangregorio T, Dall'Arche M, Gabelli M, Tretti C, Biffi A, Bresolin S, Savoia A. Identification and Functional Study of a New Germline Variant in Mecom Gene [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/identification-and-functional-study-of-a-new-germline-variant-in-mecom-gene/. Accessed September 29, 2023.
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