Two genes required for diabetes in BB rats. Evidence from cyclical intercrosses and backcrosses.

Jackson, Richard A.; Buse, John B.; Rifai, R; Pelletier, Daniel; Milford, Edgar L.; Carpenter, C.B.; Eisenbarth, George S.; Williams, Rachel

doi:10.1084/jem.159.6.1629

Cited by 75 publications

(22 citation statements)

References 14 publications

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“…The importance of the Gimap/IAN GTPase family for T lymphocyte survival became evident from investigations of the rat lymphopenia (lyp) gene. This recessive mutation causes severe peripheral T lymphopenia when homozygous and is an essential susceptibility locus in autoimmune models of both spontaneous diabetes mellitus (the BioBreeding diabetes prone (BB-DP) 4 rat) and eosinophilic bowel disease (the PVG-RT1 u ,lyp/lyp rat) (2)(3)(4). Positional cloning of lymphopenia identified a single base pair deletion in the Gimap5 gene.…”

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A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Carter

Dion

Schnell

et al. 2007

The Journal of Immunology

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The Gimap/IAN family of GTPases has been implicated in the regulation of cell survival, particularly in lymphomyeloid cells. Prosurvival and prodeath properties have been described for different family members. We generated novel serological reagents to study the expression in rats of the prodeath family member Gimap4 (IAN1), which is sharply up-regulated at or soon after the stage of T cell-positive selection in the thymus. During these investigations we were surprised to discover a severe deficiency of Gimap4 expression in the inbred Brown Norway (BN) rat. Genetic analysis linked this trait to the Gimap gene cluster on rat chromosome 4, the probable cause being an AT dinucleotide insertion in the BN Gimap4 allele (AT(+)). This allele encodes a truncated form of Gimap4 that is missing 21 carboxyl-terminal residues relative to wild type. The low protein expression associated with this allele appears to have a posttranscriptional cause, because mRNA expression was apparently normal. Spontaneous and induced apoptosis of BN and wild-type T cells was analyzed in vitro and compared with the recently described mouse Gimap4 knockout. This revealed a “delayed” apoptosis phenotype similar to but less marked than that of the knockout. The Gimap4 AT(+) allele found in BN was shown to be rare in inbred rat strains. Nevertheless, when wild rat DNA samples were studied the AT(+) allele was found at a high overall frequency (∼30%). This suggests an adaptive significance for this hypomorphic allele.

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confidence: 99%

A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Carter

Dion

Schnell

et al. 2007

The Journal of Immunology

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“…However, RT1-DM may be expressed codominantly (as MHC genes are) with low disease penetrance in the heterozygote state. 5 From the same reports, it is apparent that there is an autosomal recessive gene that determines the severe T-cell lymphopenia of BB rats. This gene is also required for the development of diabetes in crosses of BB rats with normal rat strains, and is not linked to the MHC.…”

Section: Discussionmentioning

confidence: 99%

Specific Class II Histocompatibility Gene Polymorphism in BB Rats

et al. 1984

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SUMMARYThe BB rat spontaneously develops insulin-dependent diabetes mellitus of autoimmune etiology. From breeding studies, one of the genes necessary for the development of diabetes in these animals is linked to RT1, the rat major histocompatibility complex. To better define the BB rat's RT1 -linked diabetogenic gene (RT1-DM), we have used restriction endonucleases BamH1 and EcoR1 in conjunction with an I-A alpha (class II mouse major histocompatibility complex) gene probe to study RT1 class II gene polymorphisms among diabetes-prone BB rats and the related non-diabetesprone BBN rats. Both BB and BBN rats are indistinguishable RT1 U by serologic methods. Four polymorphic chromosome types (la, Ib, Ha, and lib) were recognized among the control BBN rats. In contrast, all BB rats were homozygous (lla/lla). From the multiple breeding programs involved, we hypothesize that the BB rat's RT1 -linked diabetogenic gene is linked to an I-A alpha-defined gene of the type Ha chromosome. The ability to split the RT1 U of BB rats will provide a powerful tool to localize and characterize RT1-DM. DIABETES 33:700-703, July 1984.T he BB rat strain was developed by Dr. Chappel and co-workers at BioBreeding Laboratories when diabetes mellitus spontaneously developed in an outbred commercial colony of Wistar-derived rats. Their diabetes is similar to type I diabetes of man. It is characterized by insulitis and pancreatic beta cell destruction leading to hypoinsulinemia and hyperglycemia that rapidly progress to ketoacidosis and death if not treated with ex- ogenous insulin. The type I diabetes of the BB rat is of autoimmune etiology. Diabetes can be transferred to immunodeficient rats with activated splenic lymphocytes from recently diabetic BB rats 2 and can be prevented or cured with multiple forms of immunotherapy. 3 The BB rat has a severe T-cell immunodeficiency, exhibiting an almost total lack of peripheral T-cells while having a grossly normal thymus. 4 We and others have recently reported that in crosses of BB rats with normal rat strains, there are at least two genes necessary for the development of diabetes.56 One determines the T-cell lymphopenia and is inherited by simple autosomal recessive genetics. The second is associated with RT1, the rat major histocompatibility complex (MHC). To further examine the BB rat's RT1-linked diabetogenic gene, termed RT1-DM, we have studied restriction fragment length polymorphisms using an I-A alpha probe (mouse class II MHC gene) in diabetes-prone BB rats and in control BBN rats, which are non-lymphopenic, non-diabetes prone, and derive from the same original colony as the BB rats. MATERIALS AND METHODSAnimals. In 1979 spontaneous diabetes was observed in a colony of outbred Wistar rats at BioBreeding, a commercial breeding facility. These diabetic rats were interbred and became known as BB rats. They were transferred to the animal facilities of the Department of National Health and Welfare, Ottawa, Canada, where they continue to be maintained by Dr. P. Thibert. These BB rats have bee...

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“…Aside from at least one u-haplotype at the RTllocus, non-MHC related factors also seem to be involved in the development of overt diabetes (Colle et al, 1981;Stark et al, 1982;Jackson et al, 1984;Colle et al, 1986). In diabetes research using BB rats, conclusions are frequently based on studies in which diabetes-prone BB lines are compared with closely related non-diabetes-prone lines of the same RTl haplotype.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation within and between lines of diabetes-prone and non-diabetes-prone BB rats; allele distribution of 8 protein markers

1991

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SummaryTwenty-four inbred and 2 outbred lines of the BB rat have been genetically characterized by establishing the allele distribution of 8 monogenic protein markers. The marker genes are: , glyoxalase I (010-1), group specific component (Oe), and haemoglobin-,g-chain (Hbb). At least 3 linkage groups are represented by this set of markers. Genetic variation was found both within and between lines. Within-line variation was observed in 4 lines, including the 2 outbred lines. The other 22 lines could be subdivided into 4 groups, each representing a unique allele distribution pattern.

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Two genes required for diabetes in BB rats. Evidence from cyclical intercrosses and backcrosses.

Cited by 75 publications

References 14 publications

A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1

Specific Class II Histocompatibility Gene Polymorphism in BB Rats

Genetic variation within and between lines of diabetes-prone and non-diabetes-prone BB rats; allele distribution of 8 protein markers

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