Our aim is to determine molecular defects in K<sub>ATP</sub> channels caused by ABCC8 mutations in Asian Indian children with NDM by in vitro functional studies.
Each of the ABCC8 gene mutation carrier family members were diagnosed with diabetes as follows: the grandfather with type 2 diabetes at 35 years of age, the aunt with slowly-progressive insulin-dependent diabetes at 18 years of age, the mother with ketosis-onset insulin-dependent diabetes at 14 years of age, the sister with impaired glucose tolerance at 9 years of age, and the proband with transient neonatal diabetes at birth.
This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11.
Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations.
A successful transition to sulfonylurea treatment in male infant with neonatal diabetes caused by the novel abcc8 gene mutation and three years follow-up.
This is the first report of an ABCC8 nonsense mutation causing a gain-of-channel function and these findings extend the spectrum of K-ATP channel mutations observed in patients with neonatal diabetes.
Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of K<sub>ATP</sub> channels have been identified as the most common cause of human neonatal diabetes mellitus.
Genetic testing for patients identified through the Ukrainian Pediatric Diabetes Register identified KCNJ11 and ABCC8 mutations as the most common cause (52%) of neonatal diabetes.
We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus.He died of ketoacidosis.
Mutations in the pancreatic ATP sensitive K(+) channel proteins [sulfonyluea receptor 1 (SUR1) and inward rectifier K(+) channel Kir6.2 (Kir6.2), encoded by ATP-binding cassette transporter subfamily C member 8 (ABCC8) and potassium channel J11 (KCNJ11), respectively], are the most common cause of neonatal diabetes.
We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated.
Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene ('MODY13'), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e.KCNJ11, ABCC8 and INS).
Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic K(ATP) channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits.
The majority of neonatal diabetes cases are caused by mutations in the K(ATP) channel genes ABCC8 and KCNJ11, and sulfonylurea therapy is then usually superior to insulin.