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.
The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1.
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.
A successful transition to sulfonylurea treatment in male infant with neonatal diabetes caused by the novel abcc8 gene mutation and three years follow-up.
The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function.
Here we investigate the molecular mechanism by which two heterozygous mutations in the second nucleotide-binding domain (NBD2) of SUR1 (R1380L and R1380C) separately cause neonatal diabetes.
Activating mutations in genes KCNJ11 and ABCC8, which form the ATP-sensitive K+channel (K(ATP) channel), have been shown to cause transient or permanent neonatal diabetes.
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.
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.
The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes.
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.
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.
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).
Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes.