KCNJ11activating mutations in Italian patients with permanent neonatal diabetes

Abstract

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

“…2c). In agreement with this prediction, mutations at R50 impair ATP inhibition [30,[37][38][39] and can give rise to neonatal diabetes [12,30]. Mutation of either H46 or N48 might, therefore, be expected to influence the position of R50, and thereby destabilize ATP binding.…”

“…The commonest cause of permanent neonatal diabetes (PNDM) are heterozygous activating mutations in the KCNJ11, the gene encoding Kir6.2, which constitutes the pore-forming subunit of the K ATP channel in the pancreatic beta cell [7][8][9]. KCNJ11 mutations account for around 50% of cases of PNDM [7][8][9][10][11][12][13]. Some of these mutations lead to a more severe syndrome in which developmental delay and epilepsy accompany neonatal diabetes, a condition known as DEND syndrome [9].…”

Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene

“…Mutation detection in six of these patients has been previously reported [9]. The newly identified patients, known here by patient numbers nd-CH/1 (R2011H), nd-MI/1 (V59M), nd-NA/9 (R201H) and nd-TN/1 (R201H), did not show any peculiar clinical feature.…”

“…The discovery that activating mutations of KCJN11 causing permanent or transient neonatal diabetes can respond to sulfonylureas [1, 2, 4-8] opened the possibility of treating patients who have this genetic defect with oral hypoglycaemic agents. In previous studies [4,9], this report and in unpublished observations (F. Barbetti), the Italian Study Group of Early-Onset Diabetes has identified 16 unrelated subjects with eight different KCNJ11 mutations. To date, one subject with KCNJ11-related transient/relapsing neonatal diabetes [4] and ten patients from the Italian cohort of KCNJ11-related permanent neonatal diabetes mellitus have been successfully transferred from insulin to sulfonylurea.…”

Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation

“…The intronless KCNJ11 gene was amplified in three overlapping fragments (B, C and D), with a primer pair previously described for B and C fragments [4] and modified for the D fragment (D forward: 5′ ccg ctg atc atc tac cat gtc 3′; D reverse: 5′ tac cac atg gtc cgt gtg tac 3′). We identified a heterozygous R201H mutation (c.602 G→A) that arose de novo in the patient.…”