Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response...

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Permanent neonatal diabetes (PND) is a severe form of diabetes that manifests in the first six months of life.
• Mutations in specific genes, including KCNJ11 (encoding Kir6.2), are known causes of PND.
• Understanding the genetic basis of PND is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of KCNJ11 mutations in GCK-negative PND.
• To identify novel mutations in Kir6.2 associated with PND.
• To evaluate the efficacy of sulfonylurea treatment in patients with Kir6.2 mutations.

Main Methods:

• Sequencing of the KCNJ11 gene in 11 probands with GCK-negative PND.
• Analysis of identified mutations for novel and known amino acid substitutions.
• Clinical assessment of mutation carriers, including response to tolbutamide and glucose tolerance tests.
• Treatment with glibenclamide (a sulfonylurea) to assess insulin replacement therapy.

Main Results:

• Heterozygous KCNJ11 mutations were identified in seven out of 11 probands.
• Three novel (F35V, Y330C, F333I) and two known (V59M, R201H) Kir6.2 mutations were found.
• The V59M mutation was associated with neurological features.
• Mutation carriers showed insulin response to tolbutamide but not glucose.
• Sulfonylurea treatment (glibenclamide) successfully replaced insulin therapy in affected individuals, maintaining glycemic control.

Conclusions:

• Mutations in Kir6.2 are a frequent cause of PND in the studied cohort.
• Kir6.2 mutations can lead to a form of diabetes responsive to sulfonylureas.
• This highlights the potential of pharmacogenetics to guide personalized diabetes treatment, offering an oral alternative to insulin injections.