Current Genomics, Vol. 4, No. 4, 2003
Contents
Role of the Insulin Receptor Variant Forms in Human
Metabolic Disorders Pp. 295-307
Giorgio Sesti
Genetic Variations of the Hemostatic System as Risk
Factors for Venous and Arterial Thrombotic Disease Pp. 309-336
R.F. Franco , M.D. Trip
and P.H. Reitsma
The G Protein b3
Subunit Gene (GNB3) 825T Allele - a Thrifty Genotype Pp. 337-342
C.K. Naber , R. Erbel
and W. Siffert
CIITA and the MHCII Enhanceosome in the Regulation of
MHCII Expression Pp. 343-363
S. Landmann, J.-M. Waldburger, K. Masternak, A.
Muhlethaler-Mottet and W. Reith
The Vpu Protein and its Role in HIV-1 Pathogenesis
Pp. 365-377
Dinesh K. Singh, Erik Pacyniak, Darcy M. Griffin and
Edward B. Stephens
Abstracts
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Role of the Insulin Receptor Variant Forms in Human Metabolic Disorders
Giorgio Sesti
The pathophysiology of type 2 diabetes includes two apparently distinct defects i.e. impaired insulin action at the level of muscle, fat and liver, and failure in b-cells secretory capacity. Insulin action is mediated by the insulin receptor, (IR) a member of the receptor tyrosine kinase family also including the type 1 Insulin-like Growth Factor I (IGF-I) receptor (IGF-IR) and the orphan receptor Insulin Receptor-Related Receptor (IRR). IR exists in two functionally distinct isoforms differing by the absence (Ex11-) or presence (Ex11+) of a 12 amino acid sequence in the COOH-terminus of the a-subunit due to alternative splicing of exon 11. In addition to forming homodimers, IR, IGF-IR and IRR can form hybrid receptors. IR/IGF-IR hybrids bind IGF-I, but not insulin, with high affinity, and function as IGF-IR homoreceptors rather than IR homoreceptors. The function of IRR is unknown and it does not transduce signals through IR/IRR hybrids. The generation of genetically engineered knockout mice with total or tissue –specific lack of IR has been instrumental in dissecting the pathophysiological role of IR not only in classical target tissues, such as muscle and liver, but also in non-classical target tissues, such as brain and pancreatic b-cells. Some, but not all, studies have reported that expression of the low-affinity Ex11+ isoform is increased in target tissues from type 2 diabetics, thus contributing to insulin resistance. There is evidence that abundance of IR/IGF-IR hybrid receptors is increased in insulin target tissues, where they might affect insulin sensitivity by sequestering IR in a less insulin-responsive form. This review will focus on the structural and functional heterogeneity of IR and related receptors, and will discuss the studies in knockout mice lacking IR. Finally, studies addressing the potential role of IR variant forms in the development of conditions of insulin resistance, such as obesity and type 2 diabetes mellitus will be reviewed.
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Genetic Variations of the Hemostatic System as Risk Factors for Venous and
Arterial Thrombotic Disease
R.F. Franco , M.D. Trip and P.H. Reitsma
[Back to top] The G Protein b3 Subunit Gene (GNB3) 825T Allele - a
Thrifty Genotype
C.K. Naber , R. Erbel
and W. Siffert
Using a classical candidate gene approach, we have described a common C825T polymorphism in the gene GNB3, encoding the ubiquitously expressed b3 subunit of heterotrimeric G proteins. The 825T allele causes alternative splicing of the gene and the generation of a truncated but functionally active splice variant of Gb3, referred to as Gb3s. In addition, the presence of a 825T allele is predictive of an enhanced signal transduction via PTX-sensitive G proteins. Caucasian carriers of the 825T allele show a significantly increased risk for hypertension, most likely "low renin hypertension", and show an increased response to thiazide diuretics. The 825T allele comes along with an increased renal perfusion and accumulates significantly in the individuals with a strong family history of hypertension. Highest frequencies of the 825T allele (up to 80%) are found in “old” ethnicities, e.g. black Africans, African Americans, bushmen, and Australian aborigines. This suggests that enhanced G protein activation represents a thrifty genotype which might have facilitated survival in our ancestors. Frequencies of the 825T allele are significant lower in Asians (approximately 40 to 50%) and Caucasians (30%). More recent studies show that young 825T allele carriers are predisposed for obesity and this association could be confirmed across different ethnicities including young Germans, as well as Chinese and black African individuals. Moreover, there is some evidence for an association with type-2 diabetes and cardiovascular disease. Genotyping at the GNB3 locus may represent an interesting candidate in a preventive medicine because individuals at risk for obesity and hypertension can be identified early and then can counteract their genetic predisposition through changes in lifestyle.
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to top] CIITA and the MHCII
Enhanceosome in the Regulation of MHCII Expression
S. Landmann, J.-M. Waldburger, K. Masternak, A.
Muhlethaler-Mottet and W. Reith
Major Histocompatibility Complex class II (MHCII) molecules direct the development, activation and homeostasis of CD4+ T cells. Given these key functions it is not surprising that the absence of MHCII expression results in a severe primary immunodeficiency disease called MHCII deficiency or the Bare Lymphocyte Syndrome (BLS). The genetic defects responsible for BLS lie in genes encoding transcription factors required for MHCII expression. Four different MHCII regulatory genes encoding RFXANK, RFX5, RFXAP and CIITA have been identified. The first three are subunits of RFX, a ubiquitously expressed factor that binds cooperatively with other proteins to MHCII and related promoters to form a highly stable macromolecular nucleoprotein complex referred to as the MHCII enhanceosome. This enhanceosome serves as a landing pad for the MHCII transactivator CIITA. CIITA is a non-DNA binding coactivator that serves as the master control factor for MHCII expression. The highly regulated expression pattern of CIITA ultimately dictates the cell type specificity, induction and level of MHCII expression. The enhanceosome and CIITA collaborate in activating transcription by promoting histone hyperacetylation and by recruiting components of the general transcription machinery. In this review we summarize what is known about the molecular basis of BLS and what this has taught us about the mechanisms regulating transcription of MHCII and related genes. Particular attention is devoted to the structure, function and mode of action of the MHCII enhanceosome and CIITA. In addition, we focus on the highly regulated and cell type specific expression of CIITA.
[Back to top] The
Vpu Protein and its Role in HIV-1 Pathogenesis
Dinesh K. Singh, Erik Pacyniak, Darcy M. Griffin and
Edward B. Stephens
The Vpu protein of human immunodeficiency virus type 1 (HIV-1) is a small transmembrane protein that is synthesized late in the virus life cycle. Several functions have been ascribed to the Vpu protein in the life cycle of HIV-1. First, Vpu has been shown to interact with the CD4 molecule in the rough endoplasmic reticulum (RER), the receptor for HIV-1 entry, and this interaction is thought to result in re-translocation across the RER and subsequent degradation via the proteasome pathway. Secondly, Vpu has been shown to enhance virion release from infected cells by some unknown mechanism. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis (HIV-1 only causes disease in humans and chimpanzees) is still unknown. This has been primarily due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency virus isolated from chimpanzees (SIVcpz). With the recent development of the pathogenic simian-human immunodeficiency virus (SHIV)/macaque model, in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV, it will now be possible to assess the role of the vpu gene product in a relevant animal model. This review will focus on the current understanding of the structure-function relationships of Vpu protein and the use of the SHIV model to assess the role of Vpu in HIV-1 pathogenesis.