The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes

Alberto Pugliese, Markus Zeller, Alarico Fernandez, Laura J. Zalcberg, Richard J. Bartlett, Camillo Ricordi, Massimo Pietropaolo, George S. Eisenbarth, Simon T. Bennett, Dhavalkumar D. Patel

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Abstract

Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS rnRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.

Original languageEnglish
Pages (from-to)293-297
Number of pages5
JournalNature Genetics
Volume15
Issue number3
DOIs
StatePublished - Mar 1 1997

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Minisatellite Repeats
Type 1 Diabetes Mellitus
Thymus Gland
Insulin
Genes
Islets of Langerhans
Pancreas
Messenger RNA
Glutamate Decarboxylase
Class 8 Receptor-Like Protein Tyrosine Phosphatases
Gene Expression
Proinsulin
Autoantigens
Fetal Development
Autoimmune Diseases
Rodentia
Chromosomes
Alleles

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. / Pugliese, Alberto; Zeller, Markus; Fernandez, Alarico; Zalcberg, Laura J.; Bartlett, Richard J.; Ricordi, Camillo; Pietropaolo, Massimo; Eisenbarth, George S.; Bennett, Simon T.; Patel, Dhavalkumar D.

In: Nature Genetics, Vol. 15, No. 3, 01.03.1997, p. 293-297.

Research output: Contribution to journalArticle

Pugliese, Alberto ; Zeller, Markus ; Fernandez, Alarico ; Zalcberg, Laura J. ; Bartlett, Richard J. ; Ricordi, Camillo ; Pietropaolo, Massimo ; Eisenbarth, George S. ; Bennett, Simon T. ; Patel, Dhavalkumar D. / The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. In: Nature Genetics. 1997 ; Vol. 15, No. 3. pp. 293-297.
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AU - Zeller, Markus

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AU - Zalcberg, Laura J.

AU - Bartlett, Richard J.

AU - Ricordi, Camillo

AU - Pietropaolo, Massimo

AU - Eisenbarth, George S.

AU - Bennett, Simon T.

AU - Patel, Dhavalkumar D.

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AB - Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS rnRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.

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