A polygene network model for the complex pathological phenotypes of collagen disease.

Almost 70 years after the description of 'collagen disease' by P. Klemperer et al., it is still controversial whether the diversity and similarity of pathological manifestations among the collagen diseases depends on ambiguity in diagnosis or is an intrinsic quality of the collagen diseases themselves. A genome wide analysis of the MRL mouse models of collagen disease may shed some light on the complex pathological manifestations. Study of the susceptibility loci to each type ofcollagen disease (such as glomerulonephritis, vasculitis, arthritis, sialoadenitis and dacryoadenitis) in the mice, revealed that these lesions developed because of a cumulative effect of multiple gene loci, none of which can induce the related phenotype alone. This may indicate that collagen disease develops in 'a polygenic system', as proposed by K. Mather in 1949. Each lesion in the mice developed because of an additive effect of the polygenes, which is also, in part, hierarchical. Some of the polygenes seemed to be common to those in other collagen diseases as well. Some of the positional candidate genes involved an allelic polymorphism in the coding or promoter regions, thus possibly causing a qualitative or quantitative difference in their function, respectively. As a result, a particular combination of the polygenes with such an allelic polymorphism may thus play a critical role in leading the cascade reaction to developing collagen disease, and also the regular variation in the pathological manifestations. We herein describe this as a polygene network of collagen disease.