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Kir6.2 Mutations Are a Common Cause of Permanent Neonatal Diabetes in a Large Cohort of French Patients

¹ Centre National de la Recherche Scientifique UMR 8090, Institute of Biology and Pasteur Institute, Lille, France
² Pediatric Endocrinology and Diabetes Unit, Institut National de la Santé et de la Recherche Médicale (INSERM) EMI 0363, Hôpital Necker Enfants Malades, Paris, France
³ Genetic Biochemistry, Hôpital Robert Debré, Paris, France
⁴ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
⁵ Pediatric Endocrinology and Diabetes Unit, INSERM U457, Hôpital Robert Debré, Paris, France
⁶ Genomic Medicine, Imperial College, Hammersmith Hospital, London, U.K

Permanent neonatal diabetes (PND), requiring insulin within the first months of life, is unexplained at the molecular level in most cases. It has very recently been shown that heterozygous activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive K⁺ channel involved in the regulation of insulin secretion, cause PND. In the present study, we screened the KCNJ11 gene for mutations in French patients with PND. Patients were recruited through the French network for the study of neonatal diabetes. Seventeen at-term babies with a median age at diagnosis of diabetes of 64 days (range 1–260) were included. We identified in nine patients seven heterozygous nonsynonymous mutations: three of them (V59M, R201C, and R201H) were already described, and the four novel mutations resulted in an amino acid change of Kir6.2 at positions F35L, G53N, E322K, and Y330C. More patients with a Kir6.2 mutation (six of nine) were reported to have a smaller birth weight than those without mutation (two of eight). Although Kir6.2 mutation carriers do not represent a phenotypically specific form of PND, an impaired function of Kir6.2 is associated with in utero insulin secretory insufficiency and growth retardation. In conclusion, we confirmed that Kir6.2 mutations are a common cause (53%) of PND in Caucasians.

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