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

• Published in: Acta diabetologica 2024-02, Vol.61 (2), p.189-194
• Main Authors: Kavitha, Babu, Srikanth, Kandi, Singh, Deepshikha, Gopi, Sundaramoorthy, Mohan, Viswanathan, Chandra, Nagasuma, Radha, Venkatesan
• Format: Article
• Language: English
• Subjects: Amino acid sequence; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; DNA; Frameshift Mutation; Genetic analysis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases - genetics; Internal Medicine; Localization; Medicine; Medicine & Public Health; Metabolic Diseases; Molecular modelling; Mutation; Neonates; Nkx2.2 protein; Nucleotide sequence; Original Article; Phenotypes; Protein structure; Proteins; Structure-function relationships; Tertiary structure; Transcription Factors - genetics
• ISSN: 1432-5233; 0940-5429; 1432-5233
• DOI: 10.1007/s00592-023-02192-y

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.