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Identification of a novel mutation in thyroxine-binding globulin (TBG) gene associated with TBG-deficiency and its effect on the thyroid function

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Abstract

Purpose

This study presents a case of familial transmission of thyroxine-binding globulin (TBG) deficiency. The SERPINA7-gene which codes for TBG is located on the X-chromosome (Xq21-22). More than 45 mutations have been reported to cause TBG- deficiency from various countries, but none from India so far. Genetic analysis of SERPINA7 gene was carried out to determine the cause of low TBG levels in one family.

Methods

DNA samples of the propositus and the family members were subjected to Polymerase Chain Reaction (PCR) followed by direct sequencing. Allele-specific PCR and Next-gen sequencing (NGS) were employed to confirm the site of the mutation. Thyroid function tests were estimated by Radioimmunoassay (RIA) and Immunoradiometric assay (IRMA) kits. X-chromosomal inactivation status was analyzed in the female members harboring the mutation.

Results

A mutational screening in this family revealed a novel frame-shift mutation S353Q, 354fs3X in the exon 4 of the SERPINA7 gene which will be referred to as TBG-complete deficiency-India (TBG-CD-Ind). One out of four female family members harboring the mutation showed selective X-chromosomal inactivation. The affected family members were clinically euthyroid initially, showed changes in the thyroid function when tested after a long time span. However, the changes in the thyroid function in the affected family members had an autoimmune etiology.

Conclusion

This study presents the first report of TBG-CD from India wherein a novel frameshift mutation referred to as TBG-CD-Ind (S353Q, 354fs3X) in the SERPINA7 gene was detected. No apparent association was identified between thyroid function and the TBG-mutation in the affected subjects. A detailed biochemical and genomic testing to determine the exact cause of discordant TFT in the patients would certainly aid in the unequivocal diagnosis of the thyroid function and for the precise individualized treatment.

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Acknowledgements

Authors wish to thank Dr. P.K.M. Koya for his support in the statistical analysis of the data.

Funding

This study did not receive any specific fund or grant.

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Authors and Affiliations

  1. Radiation Medicine Centre, Bhabha Atomic Research Centre, TMH Annexe Building, Parel, Mumbai, 400012, India

    S. Gawandi, K. Jothivel & S. Kulkarni

  2. Homi Bhabha National Institute , Bhabha Atomic Research Centre, Mumbai, India

    S. Kulkarni

Authors
  1. S. Gawandi
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  2. K. Jothivel
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  3. S. Kulkarni
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Contributions

Conceptualization: SG, SK; Methodology, Data curation: SG, KJ; Writing—original draft: SG; Writing—review and editing: SK; Project administration: SK.

Corresponding author

Correspondence to S. Kulkarni.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The clinical investigations were in accordance with the Ethical Standards of the Helsinki Declaration. The study was approved by Institutional Medical Ethics Committee (RMC-IMEC-P6/Feb/2018/OPA (233616)).

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Written informed consent was obtained from the patients and healthy volunteers before any clinical procedures.

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Gawandi, S., Jothivel, K. & Kulkarni, S. Identification of a novel mutation in thyroxine-binding globulin (TBG) gene associated with TBG-deficiency and its effect on the thyroid function. J Endocrinol Invest 45, 731–739 (2022). https://doi.org/10.1007/s40618-021-01697-z

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  • DOI: https://doi.org/10.1007/s40618-021-01697-z

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