This allele was identified on a C57BL/6J and PL/J mixed background containing the CD18 hypomorphic alleles Itgb2tm1Bay.
Mapping and Phenotype information for this QTL, its variants and associated markers
Linkage analysis was performed on 343 animals from a (PL/J-Itgb2<tm1Bay> x C57BL/6J-Itgb2<tm1Bay>)F1 x PL/J-Itgb2<tm1Bay> backcross to identify QTLs associated with psoriasis susceptibility. Parental strain PL/J-Itgb2<tm1Bay> is CD18 hypomorphic and displays spontaneous development of a skin disease resembling psoriasis. Parental strain C57BL/6J-Itgb2<tm1Bay> is CD18 hypomorphic and does not develop psoriasis. Genome scan was performed using 83 microsatellite markers at an average resolution of 17 cM.
Significant linkage to psoriasis time of onset and severity in CD18 hypomorphic backcross animals mapped to 18 cM on mouse Chromosome 10 near D10Mit86 and D10Mit214 (LOD=10.2). This locus is named Psrs1 (psoriasis susceptibility 1). PL/J-derived allelesat Psrs1 promoted psoriasiform skin disease in backcross animals. A second locus, Psrs2 (psoriasis susceptibility 2), at 63 cM near D10Mit233 and D10Mit14 is linked to psoriasis susceptibility and severity. PL/J-derived alleles at Psrs2 confer increased psoriasis susceptibility and severity in CD18 hypomorphic backcross animals. Both Psrs1 and Psrs2 exhibit additive inheritance and do not appear to interact.
Psrs3 (psoriasis susceptibility 3) mapped to 41.5 cM on mouse Chromosome 6 near D6Mit67 (LOD=3.1) in linkage to psoriasis time of onset. This locus also exhibits suggestive linkage to psoriasis susceptibility (LOD=1.6) and severity (LOD=1.4). PL/J-derived alleles at Psrs3 promote psoriasis in CD18 hypomorphic backcross animals. The Psrs3 QTL interval is flanked by D6Mit4 (33.5 cM) and D6Mit25 (65 cM).
Significant linkage to psoriasis severity, named Psrs4 (psoriasis susceptibility 4), mapped to 25 cM (46 Mb) on mouse Chromosome 1 near D1Mit236. A second locus named Psrs5 (psoriasis susceptibility 5) is linked to psoriasis severity and mapped to 107 cM (191 Mb) near Tgfbm2 (formerly D1Mit17) and D1Mit292. PL/J-derived alleles at Psrs4 and Psrs5 confer increased disease severity.
Psrs6 (psoriasis susceptibility 6) is located at 66.6 cM on mouse Chromosome 4 near D4Mit170. This locus interacts with Psrs4 on mouse Chromosome 1. Animals homozygous for PL/J-derived alleles at both Psrs4 and Psrs6 exhibit significantly increased psoriasis susceptibility.
Significant linkage to psoriasis severity, designated Psrs7 (psoriasis susceptibility 7), mapped to 22 cM - 24 cM (44 Mb - 46 Mb) on mouse Chromosome 18 near D18Mit194 and D18Mit35. PL/J-derived alleles at Psrs7 confer increased psoriasis severity.
Psoriasis susceptibility QTLs Psrs1 (18 cM, chr10) and Psrs3 (41.5 cM chr6) were previously identified in a backcross derived from PL/J-Itgb2<tm1Bay> and C57BL/6J-Itgb2<tm1Bay>. Parental strain PL/J-Itgb2<tm1Bay> is CD18 hypomorphic and displays spontaneous development of a skin disease resembling human psoriasis. In contrast, the same CD18 hypomorphic allele, Itgb2<tm1Bay>, on a C57BL/6J genetic background does not result in psoriasis.
The current study confirmed and localized Psrs1 (aka Pds1) usingcongenic line analysis. When a PL/J-derived genetic interval surrounding Prsr1 is introgressed onto a C57BL/6J-Itgb2<tm1Bay> psoriasis-resistant background, the resulting congenic animals recapitulate the psoriasis-susceptible phenotype of PL/J-Itgb2<tm1Bay>. Analysis of four congenic lines narrowed the Psrs1 interval to a 9 cM region between D10Mit126 (21 cM) and D10Mit194 (29 cM). This region contains 46 known genes. Authors mention Cd24a (26 cM), Gja1 (29 cM) and Fyn (25 cM) as some potential candidatesfor Psrs1. The Psrs1 locus is syntenic to human Chromosome 6q16 and 6q21-q24. Although no psoriasis QTLs have been mapped to these regions in humans, autoimmune type 1 diabetes and rheumatoid arthritis have been associated with human 6q21.
The Psrs1 locus confers a high incidence of psoriasis (>87.5% at 16 weeks of age) and arthritis (>75% at 16 weeks of age) in congenic animals. The psoriasis phenotype is progressive and includes severe erythema, scale and crust formation onthe back skin, hyperplasia of the epidermis, hyperorthokeratosis, subcorneal microabscesses and diffuse inflammatory cell infiltration in the dermis with increased numbers of CD4+ cells, macrophages. Skin sections stained strongly for TNF-alpha. In addition, congenic animals displayed arthritic joint swelling, erythema and cartilage damage of the ankle joints and tarsometatarsal and metatarsophalangeal paw joints.
Psrs3 (psoriasis susceptibility 3) is associated with earlier psoriasis onset. Interestingly, congenic animals carrying PL/J-derived DNA from D6Mit274 (20.5 cM) to D6Mit14 (71.2 cM), which includes the Psrs3 locus, on a C57BL/6J-Itgb2<tm1Bay> genetic background do not develop psoriasis or arthritis by 16 weeks of age. Apparently, Psrs3 is notsufficient on its own to promote psoriasis and/or arthritis on a C57BL/6J-Itgb2<tm1Bay> resistant background.