Lymphopenia in the BB Rat Model of Type 1 Diabetes is Due to a Mutation in a Novel Immune-Associated Nucleotide (<i>Ian</i>)-Related Gene

MacMurray, Armand J.; Moralejo, Daniel H.; Kwitek, Anne E.; Rutledge, Elizabeth A.; Yserloo, Brian Van; Gohlke, Paul; Speros, Sara J.; Snyder, B.; Schaefer, Jonathan B.; Bieg, Sabine; Jiang, Jianming; Ettinger, Ruth A.; Fuller, Jessica; Daniels, Terri; Pettersson, Anna; Orlebeke, Kimberly; Birren, Bruce W.; Jacob, Howard J.; Lander, Eric S.; Lernmark, Åke

doi:10.1101/gr.412702

Cited by 206 publications

(226 citation statements)

References 54 publications

(65 reference statements)

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“…Clinical observations have demonstrated that hypoadiponectinemia is closely correlated to endothelial dysfunction in peripheral arteries (30,35,45,57,61). Our in vitro studies demonstrated that aortic vascular rings from Ad knockout mice manifest endothelial dysfunction in terms of increased superoxide production, decreased eNOS phosphorylation, and aberrant vasodilatory response to acetylcholine (9).…”

Section: Ad and Endothelial Dysfunctionmentioning

confidence: 71%

Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease

Tao¹,

Wang²,

Li³

et al. 2011

Antioxidants & Redox Signaling

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Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30 kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and antiischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits.

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Section: Ad and Endothelial Dysfunctionmentioning

confidence: 71%

Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease

Tao¹,

Wang²,

Li³

et al. 2011

Antioxidants & Redox Signaling

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“…After extraction, DNA was subject to PCR using GoTaq polymerase and Well-Red Dye-labeled oligos (SigmaAldrich) (MacMurray et al, 2002;Moralejo et al, 2003) for subsequent microsatellite analyses using the CEQ 8000 system (Beckman Coulter).…”

Section: Genotypingmentioning

confidence: 99%

Increased GABAA channel subunits expression in CD8+ but not in CD4+ T cells in BB rats developing diabetes compared to their congenic littermates

Mendu

Åkesson

Jin

et al. 2011

Molecular Immunology

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“…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.

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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

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Lymphopenia in the BB Rat Model of Type 1 Diabetes is Due to a Mutation in a Novel Immune-Associated Nucleotide (Ian)-Related Gene

Cited by 206 publications

References 54 publications

Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease

Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease

Increased GABAA channel subunits expression in CD8+ but not in CD4+ T cells in BB rats developing diabetes compared to their congenic littermates

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

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