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A novel stop-loss mutation in NKX2-2 gene as a cause of neonatal diabetes mellitus: molecular characterization and structural analysis

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Abstract

Aim

To identify the genetic etiology of neonatal diabetes in an infant and to elucidate the molecular mechanism of the identified mutation underlying the pathogenesis.

Methods

Genetic analysis was carried out by sequencing of known etiological genes associated with NDM. Molecular characterization was performed by constructing a identified mutation in NKX2-2 gene and  functional aspects was tested using transactivation, protein expression, DNA binding, nuclear localization assays. Structural analysis was performed by modeling the NKX2-2 protein structure.

Results

A novel homozygous frameshift mutation  c.772delC, p.Q258SFs*59 in the NKX2-2 gene was identified in a patient with neonatal diabetes. Functional studies revealed that this mutation resulted in an elongated protein sequence, affecting DNA binding activity and transcriptional function. Structural analysis suggested alterations in the protein’s tertiary structure, likely contributing to its dysfunction.

Conclusion

This study presents the first report of a stop-loss mutation in the NKX2-2 gene associated with NDM. Our findings emphasize the importance of functional and structural characterization to understand the biological consequences of such mutations. This comprehensive analysis provides insights into the molecular mechanisms underlying NDM and its clinical phenotype, which may aid in better diagnosis and management of patients with similar variants in the future.

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Acknowledgements

Authors thank the patient and her parents for giving the blood samples for the study.

Funding

This study was supported by the Indian Council of Medical Research (ICMR), India, through the project Functional Studies on Variants of Pancreatic β-cell genes (HNF1A, HNF4A, ABCC8 and KCNJ11) in monogenic diabetes—an experimental approach with clinical translational potential; grant no: No. 5/4/5–2/Diab/2020-NCD-III awarded to VR.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Centre for Advanced Research On Diabetes, Affiliated to University of Madras, #4, Conran Smith Road, Gopalapuram, Chennai, 600 086, India

    Babu Kavitha, Sundaramoorthy Gopi & Venkatesan Radha

  2. Andhra Medical College, Visakhapatnam, Andhra Pradesh, India

    Kandi Srikanth

  3. Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India

    Deepshikha Singh & Nagasuma Chandra

  4. Department of Diabetology, Madras Diabetes Research Foundation, Chennai and Dr. Mohan’s Diabetes Specialties Centre, IDF Centre of Education, Chennai, India

    Viswanathan Mohan

Authors
  1. Babu Kavitha
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  2. Kandi Srikanth
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  3. Deepshikha Singh
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  4. Sundaramoorthy Gopi
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  5. Viswanathan Mohan
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  6. Nagasuma Chandra
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  7. Venkatesan Radha
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Contributions

VR and BK conceptualized and implemented the study; BK performed and analyzed the functional data and wrote manuscript; NC and DS designed and performed structural analysis; NC analyzed the structural data; SG performed segregation analysis; KS and VM collected the clinical data and analyzed the manuscript; VR analyzed all data and corrected the manuscript. All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence to Venkatesan Radha.

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Conflict of interest

The authors declare that they have no conflict of interest.

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Informed consent was obtained from the proband parents included in the study.

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Managed by Fabrizio Barbetti.

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Kavitha, B., Srikanth, K., Singh, D. et al. A novel stop-loss mutation in NKX2-2 gene as a cause of neonatal diabetes mellitus: molecular characterization and structural analysis. Acta Diabetol 61, 189–194 (2024). https://doi.org/10.1007/s00592-023-02192-y

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  • DOI: https://doi.org/10.1007/s00592-023-02192-y

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