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Activating mutations in the KCNJ11 gene encoding the ATP-sensitive K+ channel subunit Kir6.2 are rare in clinically
Emma L Edghill1, Anna L Gloyn, Kathleen M Gillespie
1Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5AX, UK.
Insights
Activating mutations in KCNJ11, a gene for the Kir6.2 subunit, rarely cause type 1 diabetes in children diagnosed before age two. Identifying these mutations is crucial for appropriate treatment of diabetes.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Permanent neonatal diabetes can result from activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive K(+) channel.
- Some patients with these mutations are diagnosed after three months of age with ketoacidosis and hyperglycemia, mimicking type 1 diabetes.
Purpose of the Study:
- To investigate the hypothesis that KCNJ11 mutations can present clinically as type 1 diabetes.
- To screen the KCNJ11 gene for mutations in UK type 1 diabetic subjects diagnosed under two years of age.
Main Methods:
- Genetic screening of the KCNJ11 gene in 77 UK type 1 diabetic subjects diagnosed before age two.
- Analysis of mutation presence, clinical presentation, and family segregation.
Main Results:
- One patient with type 1 diabetes diagnosed at five weeks was found to be heterozygous for the KCNJ11 R201C mutation.
- A novel variant, R176C, was identified but did not cosegregate with diabetes in the family.
- The identified KCNJ11 mutations were rare in the cohort studied.
Conclusions:
- Heterozygous activating KCNJ11 mutations are a rare cause of type 1 diabetes diagnosed before two years of age.
- While rare, identifying KCNJ11 mutations in type 1 diabetes patients has significant treatment implications.
Abstract:
We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the beta-cell ATP-sensitive K(+) channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications.
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