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Identification of a novel mutation in the factor XIII A subunit in a patient with inherited factor XIII deficiency

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Abstract

Inherited factor XIII (FXIII) deficiency is an extremely rare and under-diagnosed autosomal recessive inherited coagulopathy, which is caused by genetic defects in the F13A1 or F13B gene. More than 200 genetic mutations have been identified since the first case of inherited FXIII deficiency was reported. This study aimed to identify underlying gene mutations in a patient with inherited FXIII deficiency who presented with recurrent intracerebral hemorrhage. Levels of plasma FXIII-A antigen were measured, F13A1 and F13B genes were sequenced, mutation information was analyzed, and the mutated protein structure was predicted using bioinformatics methods. Molecular genetic analysis identified four mutations of FXIII-related genes in the proband, including three previously reported mutations inherited from his parents (c.631G>A, p.Gly210Arg and c.1687G>A, p.Gly562Arg of F13A1 gene and c.344G>A, p.Arg115His of F13B gene) and a novel spontaneous mutation of F13A1 gene (c.2063C>G, p.Ser687Cys). Molecular structural modeling demonstrated that the novel Ser687Cys mutation may cause changes in the spatial structure of FXIII-A and increase its instability. In conclusion, we identified a novel and likely pathogenic mutation of the F13A1 gene, which enriched the gene mutation spectrum of inherited FXIII deficiency. The findings may provide promising targets for diagnosis and treatment of inherited FXIII deficiency.

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Research data of the study are available from the corresponding author on reasonable request.

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Acknowledgements

Zi Sheng and Yunhai Fang designed the research; Jun Peng, Jihua Qiu, and Xinsheng Zhang conducted the research; Lijie Yan collected the clinical data; Lijie Yan and Tiantian Wang analyzed the data and drafted the paper. All authors revised and approved the final version of the manuscript. This study was funded by the National Natural Science Foundation of China (82000126, 91942306, and 81770133), Shandong Medical and Health Science and Technology Development Program (202103040601), and China Postdoctoral Science Foundation (2020M672075). The authors have no competing interests.

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  1. Lijie Yan and Tiantian Wang contributed equally as co-first authors.

Authors and Affiliations

  1. Department of Hematology, Qilu Hospital of Shandong University, No. 107 Wenhua West Road, Jinan, China

    Lijie Yan, Jun Peng & Zi Sheng

  2. Shandong Blood Center, Shandong Hemophilia Treatment Center, No. 22, Shanshi East Road, Jinan, China

    Tiantian Wang, Xinsheng Zhang & Yunhai Fang

  3. Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, China

    Jihua Qiu & Zi Sheng

  4. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Jun Peng

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Correspondence to Yunhai Fang or Zi Sheng.

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The authors state that they have no interests which might be perceived as posing a conflict or bias.

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Ethics approval (No. KYLL-202205-023-1) was obtained from The Medical Ethics Committee of Qilu Hospital, Shandong University.

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The work was done in Qilu Hospital of Shandong University and Shandong Hemophilia Treatment Center.

Supplementary Information

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12185_2023_3594_MOESM1_ESM.tiff

Supplementary file1 (TIFF 26384 kb) Supplementary Fig. 1 Three-dimensional structure of mutant protein predicted by AlphaFold. A Mutant protein structure when Ser687Cys exists together with Gly210Arg in one allele. B Mutant protein structure when Ser687Cys exists together with Gly562Arg in one allele. C Local protein structure caused by Ser687Cys mutation. Yellow dashed lines represent hydrogen bonds. Hydrogen bond lengths are marked with black numbers. Residues and corresponding colors are as follows: Arg210-blue, Arg562-magentas, Cys687-orange

12185_2023_3594_MOESM2_ESM.tiff

Supplementary file2 (TIFF 26384 kb) Supplementary Fig. 1 Three-dimensional structure of mutant protein predicted by AlphaFold. A Mutant protein structure when Ser687Cys exists together with Gly210Arg in one allele. B Mutant protein structure when Ser687Cys exists together with Gly562Arg in one allele. C Local protein structure caused by Ser687Cys mutation. Yellow dashed lines represent hydrogen bonds. Hydrogen bond lengths are marked with black numbers. Residues and corresponding colors are as follows: Arg210-blue, Arg562-magentas, Cys687-orange

12185_2023_3594_MOESM3_ESM.docx

Supplementary file3 (TIFF 26384 kb) Supplementary Fig. 1 Three-dimensional structure of mutant protein predicted by AlphaFold. A Mutant protein structure when Ser687Cys exists together with Gly210Arg in one allele. B Mutant protein structure when Ser687Cys exists together with Gly562Arg in one allele. C Local protein structure caused by Ser687Cys mutation. Yellow dashed lines represent hydrogen bonds. Hydrogen bond lengths are marked with black numbers. Residues and corresponding colors are as follows: Arg210-blue, Arg562-magentas, Cys687-orange

12185_2023_3594_MOESM4_ESM.tiff

Supplementary file4 (DOCX 15 kb) Supplementary Table 1 Sequencing results of F13A1 and F13B genes in the patient'sparents

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Yan, L., Wang, T., Qiu, J. et al. Identification of a novel mutation in the factor XIII A subunit in a patient with inherited factor XIII deficiency. Int J Hematol 118, 26–35 (2023). https://doi.org/10.1007/s12185-023-03594-y

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