The Diabetes-Prone BB Rat Carries a Frameshift Mutation in<i>Ian4</i>, a Positional Candidate of<i>Iddm1</i>

Hornum, Lars; Rømer, John; Markholst, Helle

doi:10.2337/diabetes.51.6.1972

Cited by 152 publications

(146 citation statements)

References 41 publications

(32 reference statements)

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…72). T-cell lymphopenia is an essential contributing factor to autoimmune diabetes susceptibility in the BB rat strain 73,74 and is implicated in causing autoimmunity in the NOD mouse 75 .…”

Section: Regulation Of Self-reactive Receptors In Folliclesmentioning

confidence: 99%

Cellular and genetic mechanisms of self tolerance and autoimmunity

Goodnow¹,

Sprent

Groth

et al. 2005

Nature

600

465

View full text Add to dashboard Cite

The mammalian immune system has an extraordinary potential for making receptors that sense and neutralize any chemical entity entering the body. Inevitably, some of these receptors recognize components of our own body, and so cellular mechanisms have evolved to control the activity of these 'forbidden' receptors and achieve immunological self tolerance. Many of the genes and proteins involved are conserved between humans and other mammals. This provides the bridge between clinical studies and mechanisms defined in experimental animals to understand how sets of gene products coordinate self-tolerance mechanisms and how defects in these controls lead to autoimmune disease. . A significant fraction of the receptors generated by both these processes bind to one or more self components in the body -a byproduct of a deliberately random receptor-generating process. Between 20 and 50% of TCRs and BCRs generated by V(D)J recombiNature Publishing Group

show abstract

Section: Regulation Of Self-reactive Receptors In Folliclesmentioning

confidence: 99%

Cellular and genetic mechanisms of self tolerance and autoimmunity

Goodnow¹,

Sprent

Groth

et al. 2005

Nature

600

465

View full text Add to dashboard Cite

show abstract

“…Several studies have established a role for GIMAPs in the late stages of lymphocyte development and in lymphocyte maintenance. A GIMAP5-deficient rat strain exhibits severe loss of peripheral Tcells (lymphopenia) and develops spontaneous type I diabetes (11)(12)(13). GIMAP5 knockout mice have a similar phenotype, including lymphopenia, complete loss of natural killer cells, and death after 15 weeks, presumably due to liver failure (14).…”

mentioning

confidence: 99%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

GTPases of immunity-associated proteins (GIMAPs) are a distinctive family of GTPases, which control apoptosis in lymphocytes and play a central role in lymphocyte maturation and lymphocyte-associated diseases. To explore their function and mechanism, we determined crystal structures of a representative member, GIMAP2, in different nucleotide-loading and oligomerization states. Nucleotide-free and GDP-bound GIMAP2 were monomeric and revealed a guanine nucleotide-binding domain of the TRAFAC (translation factor associated) class with a unique amphipathic helix α7 packing against switch II. In the absence of α7 and the presence of GTP, GIMAP2 oligomerized via two distinct interfaces in the crystal. GTP-induced stabilization of switch I mediates dimerization across the nucleotide-binding site, which also involves the GIMAP specificity motif and the nucleotide base. Structural rearrangements in switch II appear to induce the release of α7 allowing oligomerization to proceed via a second interface. The unique architecture of the linear oligomer was confirmed by mutagenesis. Furthermore, we showed a function for the GIMAP2 oligomer at the surface of lipid droplets. Although earlier studies indicated that GIMAPs are related to the septins, the current structure also revealed a strikingly similar nucleotide coordination and dimerization mode as in the dynamin GTPase. Based on this, we reexamined the relationships of the septin-and dynamin-like GTPases and demonstrate that these are likely to have emerged from a common membrane-associated dimerizing ancestor. This ancestral property appears to be critical for the role of GIMAPs as nucleotide-regulated scaffolds on intracellular membranes. G protein | protein structure

show abstract

“…7,8 Thus far, the most conclusive data on the important role of the Ian family within the immune system come from studies of a rat model for insulin-dependent diabetes mellitus (IDDM) type I. Diabetes-prone (DP) BB rats spontaneously develop insulin-dependent diabetes resembling human type I diabetes. 9,10 The rats also exhibit lifelong T-cell lymphopenia. Functional and genetic data support the hypothesis that the gene responsible for the lymphopenia, Lyp, is also a diabetes susceptibility gene, named Iddm1.…”

Section: Introductionmentioning

confidence: 99%

hIan5: the human ortholog to the rat Ian4/Iddm1/lyp is a new member of the Ian family that is overexpressed in B-cell lymphoid malignancies

et al. 2004

View full text Add to dashboard Cite

The family of immune associated nucleotide binding proteins (Ian) is a distinct family of GTP-binding proteins conserved in plants, mice, rats and humans that are associated with immune functions, suggesting involvement in conserved defense mechanisms. Recently, the rat Ian4 (rIan4) was cloned and it appears to be identical to the gene Iddm1/lyp responsible for severe lymphopenia and the development of insulin-dependent diabetes in the BB-DP rat. Here we describe the characterization of a new human member of the Ian family: hIan5. hIan5 is highly homologous to rIan4, has a predicted molecular weight of 35 kDa and contains distinct G motifs of GTP-binding proteins (G-1 to G-4) in the N-terminus. Human Ian5 is anchored to the mitochondria by the hydrophobic COOH-terminal domain. Human Ian5 is highly expressed in lymph node and spleen. Different blood fractions show high hIan5 expression in CD4-and CD8-positive T cells and monocytes, but not in B lymphocytes. In contrast, in B-CLL (chronic lymphocytic leukemia) and mantle cell lymphoma samples, hIan5 mRNA was upregulated. The current data underline the role of hIan5 in T-lymphocyte development and function, and for the first time suggest that upregulation of Ian proteins is associated with B-cell malignancy, possibly by inhibiting apoptosis.

show abstract

The Diabetes-Prone BB Rat Carries a Frameshift Mutation inIan4, a Positional Candidate ofIddm1

Cited by 152 publications

References 41 publications

Cellular and genetic mechanisms of self tolerance and autoimmunity

Cellular and genetic mechanisms of self tolerance and autoimmunity

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

hIan5: the human ortholog to the rat Ian4/Iddm1/lyp is a new member of the Ian family that is overexpressed in B-cell lymphoid malignancies

Contact Info

Product

Resources

About