Molecular mechanism of a novel Ser362Asn mutation causing inherited FX deficiency in a Chinese family

Abstract

Factor X (FX) deficiency is an inherited autosomal recessive bleeding disorder. Here, we analyzed a proband with FX deficiency in a Chinese family. Genetic analysis revealed that the proband and his affected sister was homozygous for c.1085G>A mutation, corresponding to a Ser362Asn substitution. In vitro expression experiments showed that the FX Ser362Asn mutation led to a significant reduction in activity levels in the culture medium. This Ser to Asn substitution may change the shape of the active site. Moreover, simulations of molecular dynamics indicated that the binding energy of the FX Ser362Asn to the substrate is higher than that of wild type and the side-chain conformation of the catalytic residue His276 (His42) is changed. This impairs the conformational switch of the protein from zymogen to proteinase, thus causing the functional defect of FX protein. Our findings suggest that the Ser362Asn substitution is a pathogenic mutation that causes inherited FX deficiency.

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Acknowledgements

We thank the family for their participation in this research.

Funding

This work was supported in part by the National Natural Science Foundation, PR China (nos. 81970172, 81700182). This research was also supported by Shanxi Provincial Key Research and Development Project (no. 201803D31123) and the Natural Science Foundation of Shanxi Province (201601D202094).

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Correspondence to Linhua Yang.

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Zhang, X., Chen, K., Wang, G. et al. Molecular mechanism of a novel Ser362Asn mutation causing inherited FX deficiency in a Chinese family. Int J Hematol 112, 8–16 (2020). https://doi.org/10.1007/s12185-020-02877-y

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Keywords

  • Inherited factor X deficiency
  • Ser362Asn mutation
  • Bioinformatics analysis
  • Molecular mechanism