A focus on dominant negative variants in a series of 170 heterozygous FXI-deficient patients

IntroductionDominant-negative effects have been described for 10 F11 variants in the literature. AimThe current study aimed at identifying putative dominant-negative F11 variants. Material and methodsThis research consisted in a retrospective analysis of routine laboratory data. ResultsIn a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant-negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant-negative effect. Our findings also do not support a dominant-negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant-negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. ConclusionOur data show that for some F11 variants recognized has having dominant-negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild-type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.

Automated summary

This study aimed to identify putative dominant-negative F11 variants. Through retrospective analysis of laboratory data from 170 patients with moderate/mild factor XI deficiencies, we identified carriers of previously reported dominant-negative variants, but their FXI activities did not match with the expected dominant-negative effect. We also found a set of patients carrying heterozygous variants, including novel ones, with FXI activities suggesting a dominant-negative effect, but for most of these variants, individuals with close to half normal FXI activity were identified, indicating an inconsistent dominant effect.