Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation

E. D'Amato, P. Tammaro, T. J. Craig, A. Tosi, R. Giorgetti, R. Lorini, F. M. Ashcroft

Research output: Contribution to journalArticlepeer-review


Aims: Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (KATP) channel, cause both permanent and transient neonatal diabetes. Identification of KCNJ11 mutations has important therapeutic implications, as many patients can replace insulin injections with sulphonylurea tablets. The aim was to determine if a KCNJ11 mutation was responsible for a dominantly inherited form of diabetes mellitus, showing variability in age at diagnosis, in an Italian family. Methods: We sequenced KCNJ11 in members of a three-generation family with variable phenotypes of dominantly inherited diabetes mellitus. One had transient early-onset diabetes, one had impaired glucose tolerance during the second pregnancy, and two had young-onset diabetes. None of the subjects showed permanent neonatal diabetes or neurological symptoms. Results: A novel heterozygous mutation (c. 679C→G and c. 680A→T) was identified, resulting in a GAG→CTG (E227L) substitution in KCNJ11. Functional studies of recombinant heterozygous KATP channels revealed a small reduction in channel inhibition by ATP (IC50 of 15 μmol/l and 38 μmol/l for wild-type and heterozygous channels, respectively) and an increase in the resting KATP current. This would be expected to impair insulin secretion. The results are in agreement with the mild phenotype of the patients. Conclusions: Our results broaden the spectrum of diabetes phenotypes resulting from KCNJ11 mutations. They indicate testing for KCNJ11 mutations should be considered not only for neonatal diabetes but also for other forms of dominantly inherited diabetes with later onset, especially where these are associated with a low body mass index and low birth weight.

Original languageEnglish
Pages (from-to)651-656
Number of pages6
JournalDiabetic Medicine
Issue number6
Publication statusPublished - Jun 2008


  • Diabetes mellitus
  • KCNJ11
  • Kir6.2
  • Neonatal diabetes
  • Type 2 diabetes

ASJC Scopus subject areas

  • Endocrinology
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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