KCNJ11 encodes the Kir6.2 subunit of the ATP sensitive, inward-rectifier potassium ion channel. In pancreatic beta cells, the K-ATP channel is an octameric complex with four KCNJ11 subunits forming the channel pore and four SUR1 subunits contributing to the regulation of channel gating. Embedded in the cell membrane, these K-ATP channels play an important physiological role by regulating insulin secretion in response to blood glucose levels. Mutations in the KCNJ11 gene are associated with Hyperinsulinemic Hypoglycemia, Familial, 2 (HHF2), characterized by unregulated insulin secretion, and Permanent Neonatal Diabetes Mellitus (PNDM), a rare form of insulin secretory failure associated with intrauterine growth retardation. KCNJ11 mutations are also linked to transient neonatal diabetes mellitus and maturity onset diabetes of the young, type 13 and an increased risk of non-insulin dependent diabetes mellitus.
Alsmadi et al., (2008) carried out a case-control association study using 550 type 2 diabetes Saudi patients above the age of 60, and age-matched335 controls. Genotyping was done using molecular beacon-based real time PCR assays E23K was performed. The frequency of the K allele among the cases (231; 21%) was significantly higher than that observed among the controls (91; 13.6%). Also the GA genotype frequency in the patients was significantly higher than that observed in the controls when compared to the GG reference genotype. There was no significant difference between the cases and controls in AA genotype frequency compared to the GG reference genotype.
A paper by Qubbaj et al. (2011) gave details of a preimplantation genetic diagnosis (PGD) that was carried out on a 36 year old Saudi woman. The woman was married to her first cousin and had four children affected with congenital hyperinsulinism. Partial pancreatectomy was carried out in all four children during infancy to control their persistent hypoglycaemia. Three of the affected children later developed diabetes mellitus. Genetic testing was employed to uncover the causal mutation and a novel homozygous transversion 902G>C was discovered in the KCNJ11 gene that would result in an Arg301Pro substitution. The parents were found to be heterozygous for this mutation. After carrying out oocyte retrieval and intracytoplasmic sperm injection, the resulting embryos were subjected to PGD. The first cycle of PGD involved whole genome amplification and mutation detection along with short tandem repeat identifier analysis and this resulted in the birth of two healthy twin girls; one a carrier for the mutation and one homozygous for the wild type allele. A second cycle of PGD using haplotyping resulted in the birth of a healthy boy with a carrier haplotype.
Deeb et al. (2016) investigated Neonatal Diabetes Mellitus (NDM) patients and characterized their genetic and clinical features. The authors found 25 cases of NDM in Abu Dhabi between the years 1985-2013, giving an incidence rate of 1:29,241 live births. Of these, 23 were Permanent Neonatal Diabetes Mellitus (PNDM) cases and 2 patients had Transient Neonatal Diabetes Mellitus (TNDM). One female patient, born at term to a consanguineous family, presented with diabetic ketoacidosis at 6 weeks. She was initially treated with insulin. A genetic test revealed a heterozygous KCNJ11 R201C mutation without neurological features. She was subsequently taken off insulin and administered oral sulphonylurea (SU). Her HbA1c was 6.4% after taking SU, compared to 10-12% on insulin. At the time of this report, she had normal growth and age-appropriate developmental milestones. This case highlighted the importance of genetic testing for NDM patients.