Abstract Number: PB1204
Meeting: ISTH 2020 Congress
Background: Congenital Factor XI (FXI) deficiency is a rare bleeding disorder caused by mutations in the F11 gene, with highly heterogeneous bleeding tendency, poorly correlated with plasma FXI activity. Among different reported mutations, the majority are missense, but most were not analyzed at the mRNA level or expressed in cells. Recent studies suggest unexpected deleterious effects of nucleotide substitutions located in specific exonic cis-acting elements (ESEs), important for correct splice-site identification and distinct from the classic splicing signals.
Aims: To investigate possible effects on splicing and functional consequences of missense mutations in F11 and implications on genotype-phenotype relationships.
Methods: In 37 subjects diagnosed with FXI deficiency (FXI:C< 0.6 IU/mL) missense mutations were identified and analyzed with the ESEfinder tool (a web resource that applies defined scoring matrices to identify possible ESEs in DNA sequences) to check the effect of selected nucleotidic substitutions on binding of proteins involved in the splicing pathway (Silico Splicing prediction).
Results: Among 21 different mutations identified in our cohort, 11 were missense variants. Ten missense variants were found in heterozygosity in 27 patients, whereas compound heterozygosity was shown in 2 patients (2 missense variants and missense/intronic mutations, respectively). Through Silico Splicing prediction 6 missense mutations were found as “aberrant splicing”, i.e. introducing or deleting splicing sites (NM_000128.3: c.1252G>A; c.1693G>A; c.1721A>G; c.1786G>T; c.1822T>C; c.943G>A); 3 as “affecting splicing” i.e. affecting the score of a splicing site (c.1199C>T; c.183C>A; c.578G>A) and 2 as “no effect on splicing” (c.1052C>A; c.168T>G).
Conclusions: According to this prediction, most missense mutations can significantly and variably affect the splicing pathway. These predicted effects should be evaluated by in vitro splicing analysis to assess possible consequences on pre-mRNA processing. A correct classification of mutations is essential for understanding structure-function relationships in the corresponding protein and searching for correlations with clinical and laboratory phenotype.
To cite this abstract in AMA style:Riccardi F, Rivolta GF, Quintavalle G, Matichecchia A, Coppola A, Tagliaferri A. Missense Mutations and Predicted Effects on Splicing in Factor XI Deficiency [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/missense-mutations-and-predicted-effects-on-splicing-in-factor-xi-deficiency/. Accessed December 6, 2023.
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