Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta(2)-microglobulin-deficient mice

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in th e MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the beta (2)-microglobulin (beta M-2) class I light chain fail to express HFE and other MHC class I family proteins, and they have b een found to manifest many characteristics of the HH phenotype. To determin e whether natural genetic variation plays a role in controlling iron overlo ad, we performed classical genetic analysis of the iron-loading phenotype i n beta M-2-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still signif icant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F-1 and back-cross progeny. These results suggest the ex istence of naturally variant autosomal and Y chromosome-linked modifier loc i that, in the context of mice genetically predisposed by virtue of a beta M-2 deficiency, can profoundly influence the severity of iron loading. Thes e results thus provide a genetic explanation for some of the variability of the HH phenotype.