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Updated: Aug 17, 2025
Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
Identification and functional analysis of three novel genetic variants resulting in premature termination codons in
Yuta Imai1, Satomi Nagaya1, Yuhei Araiso1
1Department of Clinical Laboratory Science, Graduate School of Medical Science, Division of Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa, 920-0942, Japan.
Insights
Novel genetic variants causing hereditary antithrombin (AT) deficiency lead to abnormal protein aggregation and impaired secretion. These findings offer new insights into thrombophilia mechanisms and potential therapeutic strategies.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilia.
- Type I AT deficiency is characterized by reduced AT levels.
Purpose of the Study:
- Identify novel variants in hereditary AT deficiency.
- Investigate the functional impact of these variants on AT protein synthesis, secretion, and cellular localization.
Main Methods:
- Genetic sequencing to identify variants in three pedigrees.
- HEK293 cell expression system to analyze variant protein function.
- Western blot and immunofluorescence microscopy to assess protein expression, aggregation, and secretion.
Main Results:
- Identified three novel AT gene variants: c.126delC, c.165C>G, and c.546delA.
- These variants result in premature termination of AT protein synthesis.
- Abnormal AT proteins were expressed intracellularly, with aggregation observed for p.Lys43Serfs*7 and p.Tyr55* variants.
- No functional AT protein was detected in the cell culture medium, indicating impaired secretion.
Conclusions:
- The identified AT variants lead to the production of abnormal proteins that aggregate and/or inhibit secretion.
- These findings elucidate novel pathogenic mechanisms in type I AT deficiency.
- Understanding these mechanisms may inform the development of potential therapies for hereditary AT deficiency.
Abstract:
Hereditary antithrombin (AT) deficiency is an autosomal dominant inherited thrombophilia. In three pedigrees of hereditary type I AT deficiency, we identified novel variants c.126delC (p.Lys43Serfs*7), c.165C > G (p.Tyr55*), and c.546delA (p.Lys182Asnfs*102) in the open reading frame encoding AT in each patient. Each of these aberrant variants leads to premature termination of AT protein synthesis. To investigate whether these abnormal variants are involved in the pathogenesis of type I AT deficiency, we analyzed the function of these variants in HEK293 cells. Results of western blot analysis and immunofluorescence microscopy showed that all abnormal variants were expressed intracellularly, but p.Lys43Serfs*7 and p.Tyr55* protein were aggregated in the cells. These three variants were not detected in the spent culture medium, indicating that these novel variants affect protein secretion. In summary, we suggest that these variants in the AT-encoding gene are translated in the cell, but form abnormal proteins that form aggregates and/or inhibit secretion. These results provide insight into novel mechanisms of type I AT deficiency and potential therapies for the condition.
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