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DOI: 10.2337/db08-0091
© 2008 by the American Diabetes Association
Online Letters to the Editor |
Comment on: Edghill et al. (2008) Insulin Mutation Screening in 1,044 Patients With Diabetes: Mutations in the INS Gene Are a Common Cause of Neonatal Diabetes but a Rare Cause of Diabetes Diagnosed in Childhood or Adulthood: Diabetes 57:1034–1042, 2008
From Clinical Sciences, Clinical Research Center, Lund University, University Hospital Malmö Allmänna Sjukhus, Malmoe, Sweden
Corresponding author: Åke Lernmark, University of Washington, Department of Medicine, P.O. Box 357710, Seattle, WA 98195. E-mail: ake{at}u.washington.edu
In the Diabetes article by Edgehill et al. (1), the authors confirm and expand the recent demonstration that proinsulin gene (INS) mutations may cause permanent neonatal diabetes (2). The sequence analysis (1) is resolving a 30-year-old mystery in the etiology of permanent neonatal diabetes in a sibship that we published in Diabetes 20 years ago (3). The older brother was born in 1975 with diabetes recognized at 3 days of age, and in 1978 his brother was born with diabetes, which was diagnosed on the first day of life. In an attempt to understand the etiology of neonatal diabetes, we reported the following: "A sibship of two HLA-Dw3/4–positive boys who developed IDDM [type 1 diabetes] within the 1st wk of life is described. Although the HLA-D region genotype would be consistent with IDDM associated with islet autoimmunity, islet cell antibodies were negative, but both boys exhibited the presence of a novel autoantibody that reacted specifically with a conspicuous, yet unidentified, determinant in the interstitial tissue among the acinar cells. The possible relationship between this acinar nonislet autoantibody and permanent neonatal diabetes remains to be established." It is now revealed that the two boys have the same heterozygous missense mutation S101C in the INS gene (1). Their mutations most likely arose through germline mosaicism (4), as neither of the unaffected parents carried the mutation in DNA isolated from blood.
The possible explanation for why this type of mutation may cause diabetes is discussed in detail (1,2). The S101 residue is highly conserved, and it is possible that the cysteine residue in this position results in a misfolded insulin. Processing of preproinsulin to proinsulin is likely to occur; however, proinsulin may not have been converted to insulin as proinsulin, insulin, and C-peptide were low in both boys (3). It is noted that both boys had an intrauterine growth failure (3), which may be consistent with the lack of biologically active insulin during the last trimester of pregnancy, when insulin is an important fetal growth factor.
The initial interest in these two boys was the fact that they were HLA-DR3/4 positive, the highest genetic risk factor for type 1 diabetes, and that there was a family history of autoimmune disease—the father had ankylosing spondylitis, and his brother had type 1 diabetes diagnosed before the boys were born (3). However, the examination of their serum for islet cell antibodies well after birth to preclude maternal transmission (mother was antibody negative) revealed the presence of nonislet pancreatic autoantibodies (3).
In 2007, the subjects, now aged 28 and 25 years, respectively, were reexamined: they were ICA, GAD65, and IA-2 autoantibody negative and have only borderline insulin antibody values. The previously observed nonislet autoantibodies were not detected. Hence, there was no sign of autoimmunity in either subject, each of whom has been treated with daily multiple insulin injections since birth. The parents remain nondiabetic. To answer the question of whether the nonislet pancreatic autoantibodies developed because the boys where HLA-DR3/4 positive and had a β-cell deficiency caused by the S101C INS mutation will require further studies.
Received for publication January 21, 2008 and accepted in revised form January 21, 2008
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- Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, Macdonald MJ, Støy J, Steiner DF, Philipson LH, Bell GI, the Neonatal Diabetes International Collaborative Group, Hattersley AT, Ellard S: Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 57:1034–1042, 2008
[Abstract/Free Full Text] - Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI, the Neonatal Diabetes International Collaborative Group: Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 104:15040–15044, 2007
[Abstract/Free Full Text] - Ivarsson SA, Marner B, Lernmark A, Nilsson KO: Nonislet pancreatic autoantibodies in sibship with permanent neonatal insulin-dependent diabetes mellitus. Diabetes 37:347–350, 1988[Abstract]
- Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE, Rankin J, Hattersley AT, Ellard S: Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab 92:1773–1777, 2007
[Abstract/Free Full Text]
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