Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 6, Number 1, February 2005

Contents


Genetic Susceptibility to Prion Diseases in Humans and Mice Pp. 1-11
S.E. Lloyd and J. Collinge
[Abstract] [Full text article]


Gene Transfer to the Central Nervous System: Current State of the Art of the Viral Vectors Pp. 13-37
E.J. Kremer
[Abstract] [Full text article]


The MHC Genes in Psoriasis Pp. 39-43
James T. Elder, Rajan P. Nair, Michael Weichenthal, Philip Stuart, John J.Voorhees, Enno Christophers and Stefan Jenisch
[Abstract] [Full text article]


The Long and Winding Road: Searching for Non-MHC Psoriasis Susceptibility Loci Pp. 45-49
Francesca Capon and Emiliano Giardina
[Abstract] [Full text article]


The Clinical Genetics of Psoriasis Pp. 51-60
E. Campalani and J.N.W.N. Barker
[Abstract] [Full text article]




Abstracts

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Genetic Susceptibility to Prion Diseases in Humans and Mice
S.E. Lloyd and J. Collinge
[Full text article]

Prion diseases are fatal transmissible neurodegenerative disorders of both animals and humans associated with prolonged incubation periods and include scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD). The arrival of variant CJD (vCJD) and the recognition that it is causally related to BSE, to which there has been widespread dietary exposure, has lead to considerable public health concerns. According to the protein-only hypothesis, prions are principally or entirely composed of an abnormal isoform (PrP^Sc) of host-encoded cellular prion protein (PrP^C). Human prion diseases have inherited, sporadic and acquired aetiologies. The inherited prion diseases are all associated with coding mutations in the human PrP gene (PRNP) and PrP polymorphisms are known to affect susceptibility, incubation time and disease phenotype. Although PRNP is the major genetic determinant of prion disease susceptibility, it is becoming clear that other genes play an important role. Genetic studies in humans are limited by the small numbers of affected individuals and therefore to identify these genes several large mouse crosses have been analysed and multiple loci on at least eight different chromosomes now identified. To date, the regions identified are large and the identification of candidate genes remains challenging. However, the development of alternative mouse crosses offers the prospect of fine mapping, which, together with microarray analysis and increased sequence information, now makes identifying these susceptibility genes a realistic goal. Characterisation of these mouse alleles and then their human homologues may allow the identification of at-risk individuals for BSE prion infection, allow better prediction of any vCJD epidemic, and ultimately should identify new proteins and biochemical pathways which will contribute to our understanding of prion pathogenesis and provide new targets for therapeutic intervention.


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Gene Transfer to the Central Nervous System: Current State of the Art of the Viral Vectors
E.J. Kremer
[Full text article]

Neurons in the CNS establish exceedingly complex and precise networks organised via specific synaptic connections that ultimately determine the cellular basis of cognitive processes and behaviour. This fragile and intricate circuitry presents a challenging barrier for fundamental neurobiology studies or clinical gene therapy where long-term genetic modification is wanted. Small volumes, low toxicity, minimal immune reaction, slow delivery times, and preferential targeting of specific cell types in selected subregions are often sine qua non for vector-mediated gene transfer. This review addresses the state-of-the-art of gene transfer to the CNS, in particular the use of adenovirus, herpes simplex virus, adeno-associated virus, simian virus 40 (SV40), lentivirus and alphavirus vectors. The advantages and drawbacks of these molecular tools with respect to their tropism; ability to traffic via axoplasmic retrograde transport; duration of transgene expression; innate, adaptive and memory immunity; and toxicity are discussed.


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The MHC Genes in Psoriasis
James T. Elder, Rajan P. Nair, Michael Weichenthal, Philip Stuart, John J.Voorhees, Enno Christophers and Stefan Jenisch
[Full text article]

Psoriasis is a common, immunologically-mediated, inflammatory and hyperproliferative disease of the skin and joints. Available evidence indicates that a major psoriasis gene (PSORS1) resides in the major histocompatibility complex (MHC), and that several additional psoriasis susceptibility genes reside elsewhere. Identification of the PSORS1 gene has been hampered by the existence of strong linkage disequilibrium (LD) in the MHC. Because it is not possible to rely on p-values associated with single alleles or short haplotypes, we and others have addressed this problem by assessing the risk associated with long “ancestral haplotypes” vs. their recombinant descendant haplotypes (recombinant ancestral haplotype mapping). Utilizing this technique, two different groups have identified a haplotype containing HLA-Cw6, “allele 5” of corneodesmosin (CDSN), and specific alleles at six intervening genes as the most likely location for PSORS1. Recently, a multicenter collaboration has been formed to identify which of the genes (or regulatory elements) on this haplotype is the “true” susceptibility allele. This collaboration is essential, as the number of informative recombinants is small due to the proximity of the genes in question. It will also be important to entertain the possibilities that multiple genes on the same haplotype influence risk, and that multiple distinct MHC alleles/haplotypes can influence risk (allelic heterogeneity). A collaborative approach involving very large numbers of families and/or cases and controls is the best way to address both of these critical questions.


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The Long and Winding Road: Searching for Non-MHC Psoriasis Susceptibility Loci
Francesca Capon, and Emiliano Giardina
[Full text article]

It is well recognised that the Major Histocompatibility Complex (MHC) harbours the main psoriasis susceptibility locus (PSORS1, Psoriasis Susceptibility 1). Nonetheless, linkage analyses have repeatedly shown that the PSORS1 locus account for less than 50% of the disease family clustering. On this basis, it is widely agreed that additional loci must contribute to psoriasis susceptibility, either by interacting directly with or by modifying the effect of the PSORS1 gene(s). To date, at least eight putative disease susceptibility regions have been mapped outside of the MHC (PSORS2-9). However, the search for the underlying genetic determinants has been seriously hindered by the difficulty of replicating linkage to these loci. The small disease-risk conferred by non-MHC genes and the likely occurrence of genetic heterogeneity are regarded as the main factors affecting the power of linkage studies and confounding the interpretation of experimental results. Evidence supporting some non-MHC loci has been provided by their close overlap with genomic regions conferring susceptibility to other inflammatory disorders. These observations indicate that clinically distinct autoimmune diseases might share common pathogenic pathways, suggesting that future advances in the understanding of single disorders could benefit the wider research community studying common inflammatory diseases.


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The Clinical Genetics of Psoriasis
E. Campalani and J.N.W.N. Barker
[Full text article]

Psoriasis is a common chronic inflammatory disease of the skin affecting approximately 2% of Caucasians. Psoriasis has a worldwide distribution, with prevalence varying according to race and geographic location. Numerous population-, family- and twin-based studies point to a very strong genetic component of this disease. Psoriasis is a complex disease, as suggested by a very unclear and variable pattern of inheritance and a higher frequency in families of dizygotic twins than in those of monozygotic twins. So far 9 psoriasis susceptibility loci have been identified (PSORS1-9) but only three (PSORS1, PSORS2 and PSORS4) have been replicated in more than one study. The strongest genetic association has been found with the HLA-C region on the short arm of chromosome 6. Failure to reach 100% concordance in monozygotic twins points to a multifactorial aetiology of psoriasis where environmental factors play an important role in genetically predisposed individuals. Clinical, histological and ultrastructural evidence suggests that psoriasis is a T cell-mediated disease where T cell activation is followed by release of pro-inflammatory cytokines, leukocytic infiltration of the skin, abnormal keratinocyte proliferation and angiogenesis. It is not known which exogenous or endogenous antigen(s) is responsible for triggering T cell activation or which genes play a fundamental role in psoriasis. Research is being carried out in an attempt to answer these questions. Here we review the main pathogenetic and epidemiological aspects of this skin condition.