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Heterozygous Missense Mutations in the Insulin Gene are linked to Permanent Diabetes appearing in the Neonatal Period or in Early-Infancy: A report from the French ND Study Group

¹Faculty of Medicine, René Descartes Paris 5 University, Paris, France
²Inserm, U845, Necker Enfants Malades Hospital, Paris, France
³Department of Pediatric Endocrinology, Necker Enfants Malades Hospital, Paris, France
⁴CNRS, 8090, Institute of Biology, Pasteur Institute, Lille, France
⁵University of Lille 2, Lille, France
⁶Genetic Biochemistry, Robert Debré Hospital, Paris, France
⁷Pediatric Endocrinology and Diabetes, Schneider Medical Center, Petah Tikva, Israel
⁸ Department of Pediatrics, Saint-Germain en Laye Hospital, Saint-Germain en Laye, France
⁹Pediatric Endocrinology, Franco-American Hospital, Reims, France
¹⁰Pediatric Endocrinology, Hôpital Sud, Rennes, France
¹¹Genomic Medicine, Hammersmith Hospital, Imperial College, London, United Kingdom

Objective: Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe non-autoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8 which encode the two subunits of the ATP-sensitive K+ (K_ATP) channel, can cause PND. Mutations in the Insulin (INS) gene have been recently described in ND families. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a K_ATP channel mutation.

Research Design and Methods: We screened the INS gene by direct sequencing in 38 PND patients and in one child with non-autoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11 and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation.

Results: We identified 3 missense mutations in the INS gene in 4 probands. 2/4 mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent 10% of all permanent ND cases, having a later presentation of diabetes and no associated symptoms compared to cases with K_ATP channel mutations.

Conclusions: Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes, and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable as residual β-cell function is still present in some patients.

Key Words: Diabetes • Genetics • Insulin biosynthesis • Insulin gene • Mutation • Neonatal diabetes

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