Mapping and identifying genes for asthma and psoriasis.
Susceptibility genes for complex diseases are characterized by reduced penetrance, caused by the influence of other genes, the environment or stochastic events. Recently, positional cloning efforts have yielded several candidate susceptibility genes in different complex disorders such as Crohn's disease and asthma. Within a genetic locus, however, the identification of the effector gene may pose further challenges and require functional studies. I review two examples of such challenges: the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a susceptibility locus for atopy and asthma, and the study of HLA-Cw6, CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. The susceptibility locus for atopy and asthma contains two genes and only one of them is protein coding. We studied its isoform-specific expression in bronchial biopsies and in a mouse model of ovalbumin-induced inflammation of bronchial epithelia. In the PSORS1 locus, strong linkage disequilibrium between genes has made it difficult to distinguish the effects of the three nearby genes. We engineered transgenic mice with either a HCR non-risk allele or the HCR*WWCC risk allele controlled by the cytokeratin-14 promoter. The results suggested that the overexpression of HCR in mouse skin was insufficient to induce a psoriasiform phenotype, but it appeared to induce allele-specific gene expression changes that were similar to those observed in psoriatic skin.
Kere
Juha
J
Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden. juha.kere@biosci.ki.se
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C412616:CCHCR1 protein, human; C109656:CDSN protein, human; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D015236:HLA-C Antigens; C528994:HLA-C*06 antigen; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C484532:NPSR1 protein, human; C493258:PHF11 protein, human; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D051722:ADAM Proteins; C450441:ADAM33 protein, human