OBJECTIVE: The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes. RESEARCH DESIGN AND METHODS: An unexpected reduction in spontaneous type 1 diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth-derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP x double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes. RESULTS: Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes. CONCLUSIONS: This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively.
OBJECTIVE: The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDPIddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes. RESEARCH DESIGN AND METHODS: An unexpected reduction in spontaneous type 1 diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth-derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP x double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes. RESULTS: Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes. CONCLUSIONS: This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively.
Authors: Armand J MacMurray; Daniel H Moralejo; Anne E Kwitek; Elizabeth A Rutledge; Brian Van Yserloo; Paul Gohlke; Sara J Speros; Ben Snyder; Jonathan Schaefer; Sabine Bieg; Jianjie Jiang; Ruth A Ettinger; Jessica Fuller; Terri L Daniels; Anna Pettersson; Kimberly Orlebeke; Bruce Birren; Howard J Jacob; Eric S Lander; Ake Lernmark Journal: Genome Res Date: 2002-07 Impact factor: 9.043
Authors: R H Wallis; K J Wallace; S C Collins; M McAteer; K Argoud; M T Bihoreau; P J Kaisaki; D Gauguier Journal: Diabetologia Date: 2004-05-26 Impact factor: 10.122
Authors: J M Fuller; M Bogdani; T D Tupling; R A Jensen; R Pefley; S Manavi; L Cort; E P Blankenhorn; J P Mordes; A Lernmark; A E Kwitek Journal: Physiol Genomics Date: 2009-04-07 Impact factor: 3.107
Authors: John P Mordes; Laura Cort; Elaine Norowski; Jean Leif; Jessica M Fuller; Ake Lernmark; Dale L Greiner; Elizabeth P Blankenhorn Journal: Mamm Genome Date: 2009-02-10 Impact factor: 2.957
Authors: Rebecca S Tirabassi; Dennis L Guberski; Elizabeth P Blankenhorn; Jean H Leif; Bruce A Woda; Zhijun Liu; Donald Winans; Dale L Greiner; John P Mordes Journal: Diabetes Date: 2009-09-30 Impact factor: 9.461