Neonatal diabetes mellitus due to a novel variant in the INS gene

Abstract

Neonatal diabetes mellitus (NDM) is a rare condition that presents with diabetes in the first few months of life. The treatment of NDM may differ depending on the genetic etiology, with numerous studies showing the benefit of sulfonylurea therapy in cases caused by mutations in KCNJ11 or ABCC8 . Mutations in the insulin gene ( INS ) have also been identified as causes of NDM; these cases are generally best treated with insulin alone. We report a case of a female infant born small for gestational age (SGA) at late preterm diagnosed with NDM at 7 wk of life who was found by rapid whole-genome sequencing to harbor a novel de novo c.26C>G (p.Pro9Arg) variant in the INS gene. She presented with diabetic ketoacidosis, which responded to insulin therapy. She did not respond to empiric trial of sulfonylurea therapy early in her hospital course, and it was discontinued once a genetic diagnosis was made. Early genetic evaluation in patients presenting with NDM is essential to optimize therapeutic decision-making.

Computational Analysis of Deleterious nsSNPs in INS Gene Associated with Permanent Neonatal Diabetes Mellitus

“…From the literature, Laurenzano et al, in 2019, detected a P9R missense variant of the INS gene in a patient, which occurs in the signal peptide of the preproinsulin molecule in an amino acid residue that is highly conserved [32]. Also, the results of Balboa et al, in 2018, demonstrated that neonatal diabetes-associated INS mutations lead to defective beta-cell mass expansion, leading to diabetes development [9].…”

A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease

“…This observation may be explained as the introduction of an additional cysteine may result in misfolding and/or aggregation. The p.P9R ( c.26C>G ) and p.L14R are signal peptide mutations cited as a cause of NDM through β-cell dysfunction, likely due to the introduction of a large and positively-charged arginine residue, in place of a comparatively smaller proline, that confers conformational rigidity and a hydrophobic non-polar leucine residue, respectively [ 4 , 46 ]. Although p.A2T does not affect preproinsulin translocation, it impairs signal peptide cleavage and thus, prevents the production of proinsulin, resulting in MODY type 10 [ 47 ].…”