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 (Neonatal Diabetes) Study Group
- Michel Polak1,2,3,
- Aurélie Dechaume4,5,
- Hélène Cavé6,
- Revital Nimri7,
- Hélène Crosnier8,
- Véronique Sulmont9,
- Marc de Kerdanet10,
- Raphael Scharfmann1,2,
- Yael Lebenthal7,
- Philippe Froguel4,5,11 and
- Martine Vaxillaire4,5
- 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
- 8Department 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, U.K
- Address correspondence and reprint requests to Dr. Martine Vaxillaire, CNRS UMR 8090 & Institut de Biologie, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille, France. E-mail:
OBJECTIVE—Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune 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+ channel (KATP channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a KATP channel mutation.
RESEARCH DESIGN AND METHODS—We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune 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 three missense mutations in the INS gene in four probands. Two of four 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 neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with KATP 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, since residual β-cell function is still present in some patients.
- ISPAD, International Society for Paediatric and Adolescent Diabetes
- KATP channel, ATP-sensitive K+ channel
- PND, permanent neonatal diabetes
- TND, transient neonatal diabetes
- Received September 24, 2007.
- Accepted December 22, 2007.