Detection of KCNJ11 gene mutations in a family with neonatal diabetes mellitus: implications for therapeutic management of family members with long-standing disease.

BACKGROUND: Activating mutations of potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), which encodes Kir6.2 (beta-cell adenosine triphosphate-sensitive potassium [K(ATP)] channel subunit), have been associated with neonatal diabetes mellitus (NDM) in different studies. Treatment with oral sulfonylureas in place of exogenous insulin injections results in improved glycemic control in most patients carrying these mutations. Exploration of genetic causes of NDM occurring before the age of 6 months has been proposed as an important issue in identification of monogenic forms of diabetes, which might be critical in their therapeutic management, as a consequence.

METHODS: Mutation screening of the KCNJ11 gene was carried out using PCR amplification followed by direct sequencing in three family members: the proband, ND1, diagnosed at 40 days of age (current age 7 years); his sibling, ND2, diagnosed at 2 years of age (current age 14 years); and their father, ND3, diagnosed at 15 years of age (current age 35 years), who had been exclusively treated with insulin. The effect of the E227K mutation was also examined in a homology model of Kir6.2.

RESULTS: Our results revealed the presence of the heterozygous missense mutation c. 679 G/A (E227K) in all three patients, who were all able to successfully transfer from insulin injections to an oral sulfonylurea, with improved glycemic control.

CONCLUSION: We found that three members of a family with highly variable age of onset of insulin-treated diabetes, diagnosed at 40 days, 2 years, and 15 years of age, all carried the E227K mutation in KCNJ11 and could switch to an oral sulfonylurea. This mutation has been previously reported in patients with permanent and transient NDM, as well as later-onset diabetes; this report adds to the variability in phenotypic presentation and further supports genetic testing in all diabetic members of any family affected by NDM.