Abstract
The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as 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 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. 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. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. 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. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 350-352 |
| Number of pages | 3 |
| Journal | Nature Genetics |
| Volume | 17 |
| Issue number | 3 |
| DOIs | |
| State | Published - Nov 17 1997 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. / Bennett, Simon T.; Wilson, Amanda J.; Esposito, Laura; Bouzekri, Nourdine; Undlien, Dag E.; Cucca, Francesco; Nisticò, Lorenza; Buzzetti, Raffaella; Bosi, Emanuele; Pociot, Flemming; Nerup, Jørn; Cambon-Thomsen, Anne; Pugliese, Alberto; Shield, Julian P H; McKinney, Patricia A.; Bain, Stephen C.; Polychronakos, Constantin; Todd, John A.; Pozzilli, P.; Visalli, N.; Baroni, M.; Fioriti, E.; Mesturino, C.; Signore, A.; Cavallo, M.; Lucentini, L.; Matteoli, M.; Crinó, 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.; De Mattia, G.; Cassone Faldetta, M.; Laurenti, O.; Marietti, G.; Pitocco, D.; Ferrazzoli, F.; Bizzarri, C.; Ghirlanda, G.
In: Nature Genetics, Vol. 17, No. 3, 17.11.1997, p. 350-352.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele
AU - Bennett, Simon T.
AU - Wilson, Amanda J.
AU - Esposito, Laura
AU - Bouzekri, Nourdine
AU - Undlien, Dag E.
AU - Cucca, Francesco
AU - Nisticò, Lorenza
AU - Buzzetti, Raffaella
AU - Bosi, Emanuele
AU - Pociot, Flemming
AU - Nerup, Jørn
AU - Cambon-Thomsen, Anne
AU - Pugliese, Alberto
AU - Shield, Julian P H
AU - McKinney, Patricia A.
AU - Bain, Stephen C.
AU - Polychronakos, Constantin
AU - Todd, John A.
AU - Pozzilli, P.
AU - Visalli, N.
AU - Baroni, M.
AU - Fioriti, E.
AU - Mesturino, C.
AU - Signore, A.
AU - Cavallo, M.
AU - Lucentini, L.
AU - Matteoli, M.
AU - Crinó, A.
AU - Teodonio, C.
AU - Amoretti, R.
AU - Tombesi, A.
AU - Ruggeri, M.
AU - Pisano, L.
AU - Suraci, C.
AU - Pennafina, M.
AU - Boscherini, B.
AU - Stoduto, S.
AU - Fonte, M.
AU - Mancabitti, M.
AU - Multari, G.
AU - Suppa, M.
AU - De Mattia, G.
AU - Cassone Faldetta, M.
AU - Laurenti, O.
AU - Marietti, G.
AU - Pitocco, D.
AU - Ferrazzoli, F.
AU - Bizzarri, C.
AU - Ghirlanda, G.
PY - 1997/11/17
Y1 - 1997/11/17
N2 - The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as 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 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. 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. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. 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. 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.
AB - The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as 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 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. 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. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. 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. 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.
UR - http://www.scopus.com/inward/record.url?scp=16944366697&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=16944366697&partnerID=8YFLogxK
U2 - 10.1038/ng1197-350
DO - 10.1038/ng1197-350
M3 - Article
C2 - 9354805
AN - SCOPUS:16944366697
VL - 17
SP - 350
EP - 352
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 3
ER -