title: Insulin gene mutations as a cause of permanent neonatal diabetes.
abstract: We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.
authors.affiliation: Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Støy
authors.forename: Emma L
authors.initials: EL
authors.lastname: Edghill
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Honggang
authors.initials: H
authors.lastname: Ye
authors.forename: Veronica P
authors.initials: VP
authors.lastname: Paz
authors.forename: Anna
authors.initials: A
authors.lastname: Pluzhnikov
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lipkind
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Lipton
authors.forename: Siri Atma W
authors.initials: SA
authors.lastname: Greeley
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Donald F
authors.initials: DF
authors.lastname: Steiner
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics*; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011384:Proinsulin; D011498:Protein Precursors; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C013737:preproinsulin