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Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals

Item Type:Article
Title:Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals
Creators Name:Raile, K. and O'Connell, M. and Galler, A. and Werther, G. and Kuehnen, P. and Krude, H. and Blankenstein, O.
Abstract:Background: Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene. Methods: Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion. Results: The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5-16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22). Conclusion: Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.
Keywords:Age of Onset, Consanguinity, Diabetes Mellitus Type 2, Family, Gene Deletion, Heterozygote, Homozygote, Insulin, Pedigree
Source:European Journal of Endocrinology
Page Range:255-260
Date:August 2011
Official Publication:https://doi.org/10.1530/EJE-11-0208
PubMed:View item in PubMed

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