The IDDM2 type 1 diabetes susceptibility locus was mapped to(1-6) and identified as(7) allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes'. Class I alleles (26 to 69 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) ape dominantly protective(8). The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis(9,10). The mode of action of IDDM2 is complicated, however, by parent-of-origin effects(2,7,11-14) and possible allelic heterogeneity within the two defined allele classes(7,15). We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting(16). But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele / Bennett, St; Wilson, Aj; Esposito, L; Bouzekri, N; Undlien, De; Cucca, Francesco; Nistico, L; Buzzetti, R; Bosi, E; Pociot, F; Nerup, J; Cambonthomsen, A; Pugliese, A; Shield, Jph; Mckinney, Pa; Bain, Sc; Polychronakos, C; Todd, Ja; Pozzilli, P; Visalli, N; Baroni, M; Fioriti, E; Mesturino, C; Signore, A; Cavallo, M; Lucentini, L; Matteoli, M; Crino, A; Teodonio, C; Amoretti, R; Tombesi, A; Ruggeri, M; Pisano, L; Suraci, C; Pennafina, M; Boscherini, B; Stoduto, S; Fonte, M; Mancabitti, M; Multari, G; Suppa, M; Demattia, G; Faldetta, Mc; Laurenti, O; Marietti, G; Pitocco, D; Ferrazzoli, F; Bizzarri, C; Ghirlanda, G.. - In: NATURE GENETICS. - ISSN 1061-4036. - 17:3(1997), pp. 350-352. [10.1038/ng1197-350]

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele

CUCCA, Francesco;
1997-01-01

Abstract

The IDDM2 type 1 diabetes susceptibility locus was mapped to(1-6) and identified as(7) allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes'. Class I alleles (26 to 69 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) ape dominantly protective(8). The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis(9,10). The mode of action of IDDM2 is complicated, however, by parent-of-origin effects(2,7,11-14) and possible allelic heterogeneity within the two defined allele classes(7,15). We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting(16). But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
1997
Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele / Bennett, St; Wilson, Aj; Esposito, L; Bouzekri, N; Undlien, De; Cucca, Francesco; Nistico, L; Buzzetti, R; Bosi, E; Pociot, F; Nerup, J; Cambonthomsen, A; Pugliese, A; Shield, Jph; Mckinney, Pa; Bain, Sc; Polychronakos, C; Todd, Ja; Pozzilli, P; Visalli, N; Baroni, M; Fioriti, E; Mesturino, C; Signore, A; Cavallo, M; Lucentini, L; Matteoli, M; Crino, A; Teodonio, C; Amoretti, R; Tombesi, A; Ruggeri, M; Pisano, L; Suraci, C; Pennafina, M; Boscherini, B; Stoduto, S; Fonte, M; Mancabitti, M; Multari, G; Suppa, M; Demattia, G; Faldetta, Mc; Laurenti, O; Marietti, G; Pitocco, D; Ferrazzoli, F; Bizzarri, C; Ghirlanda, G.. - In: NATURE GENETICS. - ISSN 1061-4036. - 17:3(1997), pp. 350-352. [10.1038/ng1197-350]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/61182
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