Human Molecular Genetics Advance Access originally published online on February 17, 2005
Human Molecular Genetics 2005 14(7):925-934; doi:10.1093/hmg/ddi086
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Relapsing diabetes can result from moderately activating mutations in KCNJ11
1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX2 5DW, UK, 2Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LJ, UK, 3Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, UK, 4University Laboratory of Physiology, University of Oxford, OX1 4TP, UK, 5Wessex Clinical Genetics Service, NHS Trust, Southampton, S016 5YA, UK, 6Division of Human Genetics, Southampton University, Salisbury, SO16 6YD, UK, 7Wessex Regional Genetics Labs, Salisbury District Hospital, Salisbury, SP2 8BJ, UK, 8The Royal Hospital for Children, Bristol, BS2 8AE, UK, 9Genetics Institute of Austin, Texas Department of Health, Austin, Texas, TX 78705, USA and 10Department of Diabetes Endocrinology and Diabetes, The Royal Hospital for Sick Children, Edinburgh, EH9 1LF, UK
* To whom correspondence should be addressed at: Peninsula Medical School, RD & E Hospital (Wonford), Barrack Road, Exeter, EX2 5DW, UK. Tel: +44 1392406806; Fax: +44 1392406767; Email: a.t.hattersley{at}exeter.ac.uk
Received December 20, 2004; Revised February 3, 2005; Accepted February 10, 2005
Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (KATP), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7–14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC50
30 versus 7 µM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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