Insulin gene mutations as a cause of permanent neonatal diabetes

doi:10.1073/pnas.0707291104

Insulin gene mutations as a cause of permanent neonatal diabetes

Julie Støy*,
Emma L. Edghill^†,
Sarah E. Flanagan^†,
Honggang Ye*,
Veronica P. Paz*,
Anna Pluzhnikov*,
Jennifer E. Below^‡,
M. Geoffrey Hayes*,
Nancy J. Cox*,^‡,
Gregory M. Lipkind^§,
Rebecca B. Lipton^¶,
Siri Atma W. Greeley^¶,
Ann-Marie Patch^†,
Sian Ellard^†,
Donald F. Steiner*,^§,^‖,
Andrew T. Hattersley^†,^‖,
Louis H. Philipson*,^‖,
Graeme I. Bell*,^‡,^‖, and
Neonatal Diabetes International Collaborative Group**

Departments of *Medicine,
^‡Human Genetics,
^§Biochemistry and Molecular Biology, and
^¶Pediatrics, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637; and
^†Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom

Contributed by Donald F. Steiner, August 2, 2007 (received for review July 25, 2007)

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 β 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 β 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 β 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.

Footnotes

^‖To whom correspondence may be addressed. E-mail: dfsteine{at}uchicago.edu, andrew.hattersley{at}pms.ac.uk, l-philipson{at}uchicago.edu, or g-bell{at}uchicago.edu
Author contributions: J.S. and E.L.E. contributed equally to this work; N.J.C., S.E., D.F.S., A.T.H., L.H.P., and G.I.B. designed research; J.S., E.L.E., S.E.F., H.Y., V.P.P., R.B.L., S.A.W.G., and A.-M.P. performed research; A.P., J.E.B., M.G.H., N.J.C., G.M.L., and D.F.S. analyzed data; and J.S., E.L.E., D.F.S., A.T.H., L.H.P., and G.I.B. wrote the paper.
↵**Neonatal Diabetes International Collaborative Group: S. Amemiya^a, Y. Tomita^b, D. Darko^c, D. A. Doyle^d, M. Densriwiwat^e, S. Likitmaskul^e, G. Forsander^f, V. Hakeem^g, M. Kocova^h, L. Liuⁱ, M. J. MacDonald^j, T. Milenkovic^k, M. Schebek^l, and S. Wentworth^m.
The authors declare no conflict of interest.
↵ ^aFaculty of Medicine, Pediatrics, Saitama Medical University, Saitama 338, Japan
↵ ^bTokai University Hachioji Hospital, Tokyo 151-8677, Japan
↵ ^cJeffrey Kelson Centre, Central Middlesex Hospital, London NW10 7NS, United Kingdom
↵ ^dDuPont Hospital for Children, Wilmington, DE 19803
↵ ^eSiriraj Hospital, Mahidol University, Bangkok 10700, Thailand
↵ ^fQueen Silvia Children's Hospital, 416-85 Gothenburg, Sweden
↵ ^gBarnet General Hospital, London EN5 3DJ, United Kingdom
↵ ^hDepartment of Endocrinology and Genetics, 9100, Skopje, Republic of Macedonia
↵ ⁱGuangzhou Children's Hospital, Guangzhou 510120, China
↵ ^jDepartment of Pediatrics, University of Wisconsin Medical School, Madison, WI 53705
↵ ^kMother and Child Healthcare Institute of Serbia “Dr. Vukan Cupic,” 11000 Belgrade, Serbia
↵ ^lKinderkrankenhaus Park Scönfeld, 34121 Kassel, Germany; and
↵ ^m1300 East Main Street, Danville, IN 46122.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707291104/DC1.
Abbreviations:

ND,

neonatal diabetes;

LOD,

logarithm of odds;

ER,

endoplasmic reticulum.
Freely available online through the PNAS open access option.