TNF Signalling and HS

A number of other, smaller families and sporadic cases that were too small on which to perform a genome-wide screen did not show linkage to either of the candidate loci described here. Although HS is now known to be a heterogeneous disease it appears that it may be caused by mutations in genes at multiple locations making it a more complex disease than originally thought.

The linkage to chromosome 6 was narrowed down by recombinants to a small region of 6q25.2 containing only six genes. The genomic structure of each of these genes was established using sequence data from the Human Genome Browser, April 2003 freeze. Any potential alternative exons encoding a different isoform or splice variant were obtained from gene prediction programs such as Genescan and Twinscan that were annotated on the Human Genome Browser. Human aligned mRNA sequences were also used for potential new spliced iso-forms. Each of the genes was analysed by PCR and direct sequencing. Although a number of sequence changes were detected, these either did not segregate with the disease phenotype and/or were detected in normal controls, and therefore no mutations were discovered.

Another HS family linked to the centromeric region of chromosome 19 between markers D19S911 and D19S1170. This region includes 19p13.11,19p12,19p11,19q11 and 19q12 cytogenetic bands and covers 16.8 Mb of genomic DNA but contains only 14 known genes and 7 predicted genes. There were also several in silico predicted genes in the interval. There are a high percentage of zinc finger proteins in this region and is therefore composed of very repetitive sequences which often causes problems in the ability to specifically amplify genes. A large number of genes in these regions are involved in the immune and inflammatory response by activating or inhibiting proinflammatory cyto-kines. The cytokines involved, such as IL-1, IL-10, IL-6 and TNF, have roles in the development of epidermal appendages, hyperprolifera-tion and cornification of epidermal cells and initiation of immune signalling [6, 14, 15, 17, 24, 29, 38]. Therefore, a mutation in any of the genes controlling these functions could potentially underlie HS. A candidate gene approach was taken in screening some of these genes, in particular those that had potential due to their expression pattern or function. Seven genes were fully sequenced to date in the chromosome 19 region but the pathogenic mutation responsible for HS has not yet been found [64].

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